Scientists from the Cedars-Sinai Board of Governors Regenerative Medicine Institute will share groundbreaking discoveries and discuss new frontiers in research at ISSCR 2026, the annual meeting of the International Society for Stem Cell Research, July 8-11 in Montreal.

Clive Svendsen, PhD, executive director of the institute, will present new data from a clinical trial of a cell-based therapy for retinitis pigmentosa, a degenerative eye disease that is mostly untreatable. This Phase 1/2a clinical trial of a subretinal injection of a human neural progenitor cell product found that the therapy is well tolerated and results in long-term engraftment. 

Arun Sharma, PhD, director of the Center for Space Medicine Research, will participate in a session co-sponsored by Cedars-Sinai on regenerative medicine in low Earth orbit. The focus of Sharma’s talk is accelerating development of organoid-based disease modeling and stem cell therapies due to increased access to microgravity, as well as in-space biomanufacturing. 

Tynhinane Hamidouche, PhD, a postdoctoral scientist in the lab of Dmitriy Sheyn, PhD, is presenting research on a stem cell–based therapy for intervertebral disc degeneration and chronic low-back pain. Using human induced pluripotent stem cells, the team generates cells that produce the matrix material found inside the discs.

Paul Linesch, PhD, a postdoctoral scientist in the Svendsen Lab, is presenting research on an inducible DNA system, adapted using new technology developed at Cedars-Sinai, to turn specific genes on and off. The system could improve direction of stem cell differentiation and open new possibilities for cellular therapy. 

Molly Easter, PhD, a postdoctoral scientist in the lab of Tyler Pierson, MD, PhD, will present research on a rare brain development disorder linked to the GATAD2B gene, which helps control how genes turn on and off during brain growth. Using brain organoids generated from patient-specific induced pluripotent stem cells, the researchers found signs that the normal layering and patterning of the cortex may be disrupted in this disorder. 

Dhruv Sareen, PhD, associate professor of Biomedical Sciences and founding director of the Cedars-Sinai Biomanufacturing Center, is presenting research on the integration of an in situ seed plating system into the center’s manufacturing workflow to streamline production of complex induced pluripotent stem cell lines for clinical-grade and research use.

Avinash Srivastava, PhD, a biomedical scientist in the Cedars-Sinai Biomanufacturing Center, is presenting information on the center’s proprietary integrated induced pluripotent stem cell biomanufacturing platform. The platform integrates standardized manufacturing with advanced bioprocessing to facilitate the scalable production of high-quality engineered cell therapies.

Media Contact

To schedule an interview with a Cedars-Sinai expert, contact Christina Elston at christina.elston@cshs.org or 626-298-0702.

Whitson, a biochemist with more than 38 years of space and science experience at NASA, is currently vice president of Human Spaceflight for Axiom Space, the only company with human spaceflight experience on board the International Space Station. She has flown on two Axiom Space commercial astronaut missions in addition to her three NASA long-duration spaceflights.  

Whitson sat down for a “fireside chat” with Arun Sharma, PhD, director of the Cedars-Sinai Center for Space Medicine Research.

Here is an excerpt from their conversation:

Arun Sharma: What are you most excited about, sciencewise, for the next generation of Axiom Space missions?

Peggy Whitson: Part of the reason I was excited to join Axiom Space was the fact that one of their goals is manufacturing in space, and I really wanted to see some of that exciting research take that next step. I think we are going to be able to unlock microgravity, use it as a tool for expanding our capabilities and then bring that capability back to Earth.

What capabilities do you think are critical for the next generation of life science in space?

I think the most important thing is having the capability to analyze and assess on board what's happening, get the data to the ground quickly and have it already processed using orbital data centers. Orbital data centers and data architecture will allow us to do iterative science and process and analyze information in real time on board. I think that will be game changing because it will allow us to quickly take advantage of new ideas that come out of the data.

When it comes to designing experiments for research in space, what should investigators consider?

The biggest thing from a safety perspective is containment. We must be able to protect the crew. And in some cases, we're protecting what we're working on from the crew. Sometimes creating this containment can take away from the ease with which we can do investigations. So I think the right balance needs to be assessed for each investigation.

Another thing to consider is that in the past we thought we had to make everything special for space. But we found a lot of things just off the shelf will work. So take the simplest route first, and try and use as much as possible off the shelf. It costs a lot less than it does to start from scratch and develop all new hardware.

Space is going to become more accessible. So we will have a chance to learn not just how selected astronauts respond to space, but how an everyday person responds to this unique situation. Talk to us about the concept of space for everybody, and what you and Axiom Space are doing to support that vision.

One of the investigations we did on our Axiom Mission 4 (Ax-4) was called Suite Ride, and it looked at insulin response in microgravity. We studied off-the-shelf techniques for monitoring glucose, and tested stability for the insulin on board and injection techniques— demonstrating that diabetes tools operate accurately in space. That's one specific example of how we are looking at opening up access to space.

What do you see as the role of a major academic medical center like Cedars-Sinai in the space ecosystem?

Space offers some unique opportunities, and organizations like Cedars-Sinai have the capability of taking that to the next level by enabling in-space biomanufacturing of advanced materials that we cannot make on Earth to benefit patients everywhere. This research in microgravity will provide the science community the opportunity to develop disease models, helping us better understand diseases to make new drugs and drug therapies for patients. This is an important role that Cedars-Sinai plays in opening up space to other organizations and researchers by just showing them what's possible from a medical perspective.

Do you have advice for students and other trainees who might ultimately pursue careers in space medicine?

Adaptability is important. And I think collaboration is incredibly important when you're working in space. You have to be able to trust people that you're working with. You have to be able to communicate effectively.

I applied to be an astronaut for over 10 years and was rejected until the 10th year. But those 10 years were some of the most valuable because of the experience I gained. It doesn't have to be a straight line to get where you want to go if you are pursuing your goals. Take advantage of the experiences that you have and learn from them. Don't be afraid of failing. You learn from that, and then you make the next run better.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

More than 30% of clinical trials fail due to adverse drug reactions, and the up to $5,054,235.00 contract award by the Advanced Research Projects Agency for Health (ARPA-H) Computational ADME-Tox and Physiology Analysis for Safer Therapeutics (CATALYST) program, will address this longstanding challenge in drug development.

“Each year, many promising drugs fail in trials because animal tests and short-term lab studies cannot predict how medicines behave in real people over time,” said Nicholas Tatonetti, PhD, vice chair of Computational Biomedicine at Cedars-Sinai and the project's lead investigator. “These failures delay lifesaving treatments and drive up drug development costs.”

The new platform, called KronosRx, aims to reduce these failures by applying AI tools to “patient avatars”—sophisticated organoids and organ-on-chip systems derived from human stem cells—to help investigators predict drug toxicity that might otherwise harm clinical trial participants.

The avatars use tiny numbers of cells to mimic the function of whole organs and their immediate response to experimental medications. The AI models in the platform are trained using millions of anonymous patient data points from Cedars-Sinai’s extensive electronic health record network. The resulting platform can forecast an organ’s response to a medication over time—and across the diverse population of patients reflected in the Cedars-Sinai data.

“These AI systems don’t just predict whether a drug is safe or toxic; they model how risk evolves dynamically, accounting for age, a patient’s health, and other medications they might be taking,” Tatonetti said.

Investigators hope this approach will allow better predictive modeling that can evolve over time, reducing reliance on animal studies and improving safety for all patients.

“By creating a more reliable and human-relevant method for safety assessment, the KronosRx project aims to improve clinical trials and to shorten development timelines,” said Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and an investigator on the KronosRx project.

The Cedars-Sinai KronosRx team includes leaders in computational biomedical innovation, stem cell biology and health informatics.

Tatonetti is leading project integration using biomedical data science and AI-driven drug discovery methods. Svendsen is applying induced pluripotent stem cells and organ chip technologies to better understand how common drugs may cause rare neurological side effects.

Arun Sharma, PhD, director of the Cedars-Sinai Center for Space Medicine Research in the Board of Governors Regenerative Medicine Institute, is using patient-specific cardiac organoid and organ chip systems to assess drug-induced cardiotoxicity. Graciela Gonzalez-Hernandez, PhD, professor and vice chair for Research and Education in the Department of Computational Biomedicine, is advancing the project’s AI and unstructured text data integration to connect molecular and clinical phenotypes.

The ultimate goal, Svendsen said, is to make critical treatments available to patients sooner.

“This approach allows AI to continually refine its forecasts as new evidence emerges, bridging the gap between computational prediction and real-world patient outcomes,” Svendsen said.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

There are currently three types of NAMS: organoids, organ-on-chip technology, and computational, or “in silico,” models.

In an editorial published this fall in the journal Cell Stem Cell, Svendsen discussed the promise and challenges surrounding these methods. He shared some of his thoughts with the Cedars-Sinai Newsroom.

How do the various new approaches work?

Organoids are small bundles of human cells that can mimic some of the function of complete organs.  While they can be generated from some adult human organs such as the gut, these adult organoids often have limited potential for cultivation and replication.  Instead we grow organoids from induced pluripotent stem cells, or iPSCs, which are mature adult human cells that have been reprogrammed into a state where they are immortal, can be replicated indefinitely and can become almost any cell type.

In organ-on-chip models, iPSC-derived organ-specific cells are grown in specially designed chips that mimic fluid flow in the body and replicate conditions cells would experience in an actual organ. In some cases, investigators are linking different types of organ chips—brain, heart, liver—as a way to replicate a complete human system.

With in silico models, AI tools are applied to large databases of human and animal data. These tools allow us to forecast how a drug works or whether it's toxic, based on data from similar drugs that have already undergone animal or human testing.

Why do we use animals, particularly mice, for medical research?

Mice and other animals provide us with a living physiological system with organs and circulation, which is something we haven’t been able to fully replicate in a laboratory dish. They also breed and age quickly, and we have learned to genetically engineer them to mimic many human diseases and conditions.

What is the downside to mice as a stand-in for humans?

Mouse biology and human biology are different in some important ways, including at the molecular level. In one recent case, we were studying a rare disease in children that hinges on a missing gene. When we attempted to create mice with this same disease by “knocking out” that gene—nothing happened. The mice did not develop the disease. It turns out that mice have another gene with very similar functions that is missing in humans. There are millions of genetic differences between mice and humans, and the smallest one can make a huge difference.

Which of the alternative approaches is most developed?

In silico is probably farthest ahead because AI is moving so quickly and we have so much data. Investigators who want to test a new drug can apply AI tools and plug the drug into large publicly available databases to learn how cells might react to that drug. And investigators who have discovered a genetic pathway that is potentially involved in a disease can plug the changes they observed into these databases to determine which drugs might reverse those changes.

Are we ready to make the leap from animal studies to these new scientific methods?

We are entering a transition period where these new technologies are starting to be used to enable new drug development.  These technologies are very, very new and there are only a few examples of where they have been successfully used as an alternative to laboratory animal research.  However,  with many exciting studies on the way, this is set to change in the near future. Stay tuned!

What should we do in the meantime?

Right now, combining some of these new methods with animal models is the best option. A laboratory animal is a complete living specimen. An organoid or organ chip offers actual human biology. And combining AI technology, animal models and organoids to test the same theory about how an organ works, how it goes wrong or how it may react to a new drug will ultimately be incredibly powerful. If all three approaches agree, you have a much greater chance of discovering something important for human health.  

Simultaneously, we will continue to study and test whether the new methods can provide more accurate information about human biology than laboratory animals can. I believe they eventually will, because we're constantly refining and improving NAMS technology. Ultimately, this will also provide a way to tailor our treatments to individuals as we can generate their organoids or organ chips, discover successful drug interactions, and then administer that drug to the same patient.  

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

CIRM, a taxpayer-funded state agency, supports the development of treatments for an array of diseases and conditions.

“The people of California expect us to deliver on the promise of cell and gene therapy using taxpayer dollars, a trust we take seriously,” said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute at Cedars-Sinai. “With these grants, we will work toward bringing novel therapies to patients with heart disease.”

Hope for Heart Failure

One grant of more than $10 million will allow Cedars-Sinai investigators to spend the next five years studying a treatment for a common form of heart failure called heart failure with preserved ejection fraction.

More than 6 million adults in the U.S. experience heart failure, which occurs when the heart doesn’t pump enough blood to meet the body’s needs. In heart failure with preserved ejection fraction, the most common type of heart failure, the heart is too stiff to properly fill with blood. It leads to death in more than half of people who develop the condition; no medications exist to stop the disease or extend a patient’s life.

David Lefer, PhD, director of Translational Research in the Department of Cardiac Surgery in the Smidt Heart Institute, will lead preclinical studies to investigate a new RNA drug, TY1, combined with the weight loss drug semaglutide as a new, more effective way to treat heart failure with preserved ejection fraction. Investigators aim to launch clinical trials within a few years.

“Obesity is a major risk factor for heart failure with preserved ejection fraction,” Lefer said. “We hope that creating a treatment that couples the benefits of a GLP-1 drug, and the immunomodulatory benefits of the RNA exomer TY1, might reduce the risk of death from heart failure.”

New Research Into a Cause of Sudden Cardiac Death

A second CIRM grant will provide more than $10 million over the course of five years for Cedars-Sinai investigators to study arrhythmogenic cardiomyopathy (ACM), a rare, inherited heart disease. ACM is the leading cause of sudden cardiac death in athletes and young people, and no medications exist to halt its progression. The grant will fund preclinical and safety studies of a new drug that may stop the disease and even reverse the heart damage it causes.

“Many people have no idea they have ACM until they experience cardiac arrest or heart failure,” said Alessandra Ciullo, PhD, a project scientist in the Smidt Heart Institute. “We’d like to offer those patients a treatment to reverse the disease and prolong lives.”

CIRM grants have supported several studies in the Smidt Heart Institute, including research into a potential new treatment for ventricular tachycardia and a cell therapy for pulmonary arterial hypertension.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

The investigators want to study how the weakened gravitational pull in space affects the growth of organoids—small collections of cells that emulate the form and function of human organs. Scientists use organoids to model diseases and test drugs, and the hope is that they will grow more quickly in space than on Earth.

Putting Research Into Practice

“Our ultimate goal is to accelerate the progress of biological research and discovery,” said Arun Sharma, PhD, director of the Center for Space Medicine Research and research scientist in the Board of Governors Regenerative Medicine Institute at Cedars-Sinai. “Our partnership with Exobiosphere furthers Cedars-Sinai’s mission to be at the forefront of space biomedicine while deepening our understanding of how organoids develop in microgravity.”

Sharma and his colleagues hope to speed the discovery of therapies that treat medical issues astronauts experience, including bone and muscle loss and heart and immune system degradation. These discoveries could also be applied to terrestrial patients experiencing similar conditions, such as sarcopenia (muscle loss), osteoporosis (bone weakening) and cardiomyopathy (enlargement, stiffening or weakening of the heart muscle).

“Drugs that are used to treat astronauts can also benefit people on Earth, making a potential broader impact for millions of patients,” Sharma said.

Partnering to Solve Challenges of Research in Space

Microgravity offers tremendous opportunities for scientific discovery but also creates challenges that investigators don’t face on Earth. For example, when astronauts open petri dishes in space, the fluid and cells inside drift out.

However, a Cedars-Sinai study co-authored by Sharma and led by Maedeh Mozneb, PhD, from the Sharma Lab, found that in 96-well plates—rows of tiny wells much smaller than petri dishes—surface tension is strong enough to hold the contents in place.

“It was the first time that anybody has ever showed that you can take this piece of affordable hardware that’s commonly used in labs on ground and bring it to space to do cell biology research,” said Sharma, a research professor in the Department of Biomedical Sciences and the Smidt Heart Institute. “In a way, it's democratizing life sciences.”

Building on this discovery, Exobiosphere developed a research platform that automates organoid experimentation in microgravity. The hardware integrates precision liquid handling, environmental control, robotic manipulation and live imaging—capabilities that previously required intensive astronaut intervention.

"This system is designed to remove barriers for scientists," said Kyle Acierno, CEO of Exobiosphere. "By streamlining the complexity of space-based research, we’re enabling our partners to focus on the science itself—delivering data faster, with greater consistency, and at a scale that’s never been possible in orbit."

The unit, about the size of a carry-on suitcase, accommodates six 96-well plates and includes a built-in incubator, microfluidic‑based liquid dispenser, plate reader and robotic arm. While optimized for microgravity, the platform can also enhance lab productivity on Earth.

Exobiosphere’s innovative work earned it a spot in the Cedars-Sinai Accelerator+ program, which invests in startups focused on improving healthcare to help bring their products to market. Cedars-Sinai Technology Ventures also recently made a $1.4 million investment in the company and will provide mentorship from researchers.  

"As an academic medical center committed to innovation, we are thrilled to invest in a company conducting important biosciences research in space while collaborating with our colleagues at the Center for Space Medicine Research," said Nirdesh K. Gupta, PhD, managing partner of Cedars-Sinai Intellectual Property Company. "Our work together exemplifies our dedication to advancing breakthrough technologies that transform healthcare in space and on Earth."

Read more from Discoveries: Space Doctors and Stem Cell Production in Microgravity

(HSU). They are the first to enroll in the new Chuck Lorre Allied Health School, Health Artificial Intelligence PhD program in the Graduate School of Biomedical Sciences and the Master of Science in Regenerative Medicine program.

“Regardless of their chosen discipline, students in the Health Sciences University will be immersed in the healthcare environment and our clinical care continuums,” said Jeffrey Golden, MD, executive vice dean of Research and Education, director of the Burns and Allen Research Institute, and the Linda and Jim Lippman Distinguished Chair in Academic Medicine at Cedars-Sinai. “Students will train side by side with experts to advance basic, translational and clinical sciences, then witness how their efforts help shape the care Cedars-Sinai delivers.”

The students’ experience will include hands-on training from prominent experts and access to advanced technologies and innovative clinical trials.

The Cedars-Sinai Chuck Lorre Allied Health School was established in 2022 with a $30 million gift from The Chuck Lorre Family Foundation. The vocational school offers training in allied healthcare roles, starting with clinical laboratory scientists, pharmacy technicians, respiratory therapy and radiation therapy technicians.

“When the opportunity presented itself to provide training and certificates for underserved individuals in our community, which in some instances would double their salaries, I was all in,” Lorre said. “Partnering with Cedars-Sinai to create the school of allied health will allow us to see long-term impacts in our communities.”

Students in the allied health programs will receive hands-on training in a clinical setting through rotations at Cedars-Sinai and its affiliates Huntington Health and Torrance Memorial Health. The programs lead to associate degrees, bachelor’s degrees or certificates. Graduates are eligible to obtain licensure and take certification exams in their chosen fields.

“The transformational gift made by The Chuck Lorre Family Foundation meets a tremendous need for allied health specialists, both at Cedars-Sinai and in the broader Los Angeles community,” Golden said.

Alexia Furbert, a 21-year-old Los Angeles resident, is one of the first students to enroll in the pharmacy technician program in the Cedars-Sinai Chuck Lorre Allied Health School.

“When I learned about the program, I was finishing my last semester at West Los Angeles College to complete my associate degree,” Furbert said. “Feeling uncertain about my career goals, I questioned whether transferring to a four-year university was the right decision for me. This program offered an opportunity to explore potential career paths and contribute to chronically understaffed areas of healthcare.”

Also new to the Cedars-Sinai Health Sciences University is the PhD in Health Artificial Intelligence (AI), which offers rigorous training in AI algorithms and methods, with a focus on analyzing clinical data to enhance patient care.

“We are elated to welcome our incoming students, who will experience a hands‑on, active approach to teaching that reinforces AI concepts through clinical rotations and scholarly collaboration with physicians and medical staff,” said Graciela Gonzalez-Hernandez, PhD, director of the Graduate Program in Artificial Intelligence. “Graduates will be positioned to directly improve healthcare and patient outcomes through the rigorous development and deployment of AI algorithms and software.”

Another new offering is the Master of Science in Regenerative Medicine, a 20-month program where students focus on stem cell research that can be used to both model and treat human diseases. The curriculum will focus on three professional paths: cell biomanufacturing, academic research into stem cell biology and learning about how stem cells can be used with different clinical specialties.

“We designed the master’s program to teach students about regenerative medicine and how stem cells hold an interesting promise for medicine,” said Wafa Tawackoli, PhD, director of Education and Training at the Board of Governors Regenerative Medicine Institute. “We are focused on giving these students an advantage as they move forward in their chosen career paths through a carefully designed curriculum. Everything we do is tailored to the future.”

The university offers other graduate degrees, including a PhD in Biomedical Sciences, that merges scientific and translational medicine curricula with mentoring by researchers and clinicians, a Master of Science in Health Systems and a Master of Science in Magnetic Resonance in Medicine.

The university also is home to several professional training programs, including nondegree educational certifications, formal trainings, internships and other ongoing opportunities to benefit students and professionals at all levels of their careers.

“We are eager to welcome our new and returning students,” Golden said, “and for them to begin their journey of understanding human diseases, how to diagnose them and how to determine the best treatments for individual patients.”

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“Previous studies have shown that transfusions of blood or plasma from young mice improved cognitive decline in older mice, but that is difficult to translate into a therapy,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and senior author of the study. “Our approach was to use young immune cells that we can manufacture in the lab—and we found that they have beneficial effects in both aging mice and mouse models of Alzheimer’s disease.”

The immune cells, called mononuclear phagocytes, circulate throughout the body disposing of harmful substances, but become less effective as we age.

The investigators used human induced pluripotent stem cells, which are adult cells that have been taken “back in time” to an early embryonic state, to generate young mononuclear phagocytes. When the young cells were infused into aging mice or a mouse model of Alzheimer’s disease, investigators noted several important changes.

First, the mice receiving the young cells performed better on memory tests than mice without cell treatment. These mice were also found to have more “mossy cells” in the hippocampus, a brain region critical for learning and memory.

“The numbers of mossy cells decline with aging and Alzheimer’s disease,” said Alexendra Moser, PhD, a project scientist in the Svendsen Lab and lead author of the study. “We did not see that decline in mice receiving young mononuclear phagocytes, and we believe this may be responsible for some of the memory improvements that we observed.”

Mice receiving the young mononuclear phagocytes also had healthier immune cells, called microglia, in their brains. These microglia use long thin branches to detect and clear debris and damaged cells. The branches shrink and retract due to aging and Alzheimer’s disease, but they remained long and healthy in mice receiving the therapy.

The mechanism behind the effects in the brain remain to be established. As the young mononuclear phagocytes did not appear to enter the brain, investigators believe the cells may have worked indirectly.

The cells could have released antiaging proteins or even tiny particles called extracellular vesicles, which are small enough to enter the brain. Or they could have absorbed pro-aging factors from the blood to keep them out of the brain. The mechanism of protection is the focus of ongoing studies to determine the most effective way to turn these findings into a therapy that could be used in a clinical trial in patients. 

“Because these young immune cells are created from stem cells, they could be used as personalized therapy with unlimited availability,” said Jeffrey A. Golden, MD, executive vice dean for Education and Research. “These findings show that short-term treatment improved cognition and brain health, making them a promising candidate to address age- and Alzheimer’s disease-related cognitive decline.”

Additional authors include Luz Jovita Dimas-Harms, Rachel M. Lipman, Jake Inzalaco, Shaughn Bell, Michelle Alcantara, Erikha Valenzuela, George Lawless, Simion Kreimer, Sarah J. Parker, and Helen S. Goodridge.

Funding: This work was supported by the Universal Sunlight Foundation, the Cedars-Sinai Center for Translational Geroscience, and the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“Organoids are three-dimensional clumps of cells—in this case heart or brain cells,” said Arun Sharma, PhD, director of the Cedars-Sinai Center for Space Medicine Research. “To create them, we reprogram skin or blood cells into stem cells and then turn the stem cells into the heart or brain cells that will form the organoids.”

Organoids, which have thus far only been produced on Earth, are less than 1 millimeter in size and are usually too small to see with the naked eye. But they pack a big scientific punch.

“We can create thousands of these organoids in just weeks, allowing us to model disease and test drugs at a scale we would not be able to achieve otherwise,” said Sharma, also a research scientist in the Board of Governors Regenerative Medicine Institute, Smidt Heart Institute, and Cedars-Sinai Cancer, and associate professor of Biomedical Sciences at Cedars-Sinai.

The cells will travel to space as part of NASA’s SpaceX 33rd commercial resupply services mission to the International Space Station, the sixth mission in which Cedars-Sinai has participated. This is the third mission funded via a NASA In-Space Manufacturing Award in partnership with Axiom Space, a Houston-based company developing space infrastructure. Some firsts from previous missions included the introduction of DNA into stem cells in space, use of off-the-shelf terrestrial lab hardware for space biosciences research, and the production of stem cells in space, Sharma said.

Sharma, a specialist in heart biology, uses organoids to study the effects of cancer therapies on the heart. Heart organoids can also be used to test therapies that might improve heart function, and to study various types of heart disease such as congenital heart defects.  

Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and a collaborator on the mission, studies brain organoids.

“My lab is focused on the study of neurodegenerative diseases such as ALS, Huntington’s disease and Parkinson’s disease, and we use brain organoids as a tool for modeling these diseases,” Svendsen said. “Creating these organoids in space is potentially a step toward accelerating our work and gaining better understanding of these diseases.”

Sharma said there are potential advantages to growing organoids in space.

“On Earth, gravity compresses these organoids, which are three-dimensional spheres,” Sharma said. “In space, gravity is reduced to almost nothing, what we call microgravity, and we believe that organoids will grow better under these conditions. They might develop new blood vessels that we aren’t able to develop on Earth, organize themselves in unique ways, or maybe even harbor different cell types that we can only develop in microgravity.”

Maedeh Mozneb, PhD, associate director of the Center for Space Medicine Research, and Sharma Lab research associate Madelyn Arzt will travel to Florida to prepare the cells for launch.

The stem cells, obtained from the Allen Institute for Cell Science, will be frozen for the trip to space and will travel aboard a SpaceX rocket in a “plate habitat” created by BioServe Space Technologies in Colorado. Once the cells reach the space station, they will be maintained by astronauts, who will change the nutrients that allow the organoids to grow and photograph the organoids using microscopes, Sharma said.

After approximately one month, the organoids will be sent back to Cedars-Sinai investigators for analysis of their size, shape, genetics and other factors. And despite the tiny size of the organoids, Sharma and his team are dreaming big.

“A dream of mine is to have a lab in space that is parallel with the labs that we have here on Earth,” Sharma said. “That would allow us to create organoids and explore biomedical applications like bioprinting of artificial heart, brain and muscle tissues in space in ways that we may not be able to on Earth.”

Next up, the team will be working on experiments funded through a new grant from the National Institutes of Health to explore using microgravity to model accelerated inflammation and aging in organ chip models of the heart, gut, and brain.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

In a study published in the peer-reviewed journal Cell Stem Cell, investigators detail how they created “ALS on a chip” and the clues the specialized laboratory chip has already produced about nongenetic causes of the disease, also known as Lou Gehrig’s disease.

The work builds on previous studies where adult cells from ALS patients were reverted into stem cells. The cells were then pushed forward to produce motor neurons, which die in the disease, causing progressive loss of the ability to move, speak, eat and breathe.

In this study, the motor neurons from ALS patients were seeded into the top channels of microengineered chips. Cells that make up the blood-brain barrier were seeded into the bottom channels of the chips. The two channels are connected through a porous membrane that allows investigators to flow fluids through the chips in order to mimic blood flow.

Investigators created a second group of the specialized chips using cells from individuals who did not have ALS, then used advanced technologies to analyze more than 10,000 genes in the motor neurons in both groups of chips.

“In our early work, we couldn’t detect many differences between the motor neurons of patients with ALS and those from healthy individuals,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and senior author of the study. “But those studies employed traditional lab culture that is static like a pond. In the body, blood vessels provide constant fluid flow to bring in nutrients and take away waste—and may even provide other types of support to motor neurons.”

In the specialized chips, the motor neurons matured more completely than they would in a static dish, and investigators could detect distinct differences in the cells from patients with ALS.

“We were intrigued to find that signaling for glutamate, a chemical that sends excitatory messages between neurons, was altered in the ALS motor neurons,” Svendsen said. “Excessive release of glutamate has long been considered a possible cause of ALS, and one of the few drugs approved to treat the disease targets this neurotransmitter. The changes we found don’t seem to cause any issues for the motor neurons when they are young, but over many years it is possible that this increased glutamate signaling may be part of why motor neurons die in ALS.”

Svendsen said that while these results are exciting, the team’s next task is to determine whether this increased glutamate signaling directly leads to the dysfunction or death of the cells. He also noted that glutamate is likely only one piece in a much larger puzzle that underlies the cause of ALS.

“These models allow us to better understand the very earliest stages of the disease process,” Svendsen said. “We haven’t connected all the dots yet, but based on these findings we have a model that will allow us to test our theories. If we can show that glutamate signaling eventually makes the ALS motor neurons sick, for instance, we can apply drugs to the blood vessel side of the chip to mimic a clinical trial. Those experiments are underway.”

Additional authors include Deepti Lall, Michael Workman, Samuel Sances, Briana N. Ondatje, Shaughn Bell, George Lawless, Amanda Woodbury, Dylan West, Amanda Meyer, Andrea Matlock, Vineet Vaibhav, and Jennifer E. Van Eyk.

Funding: This work was supported by NIH-NCATS grants 1UG3NS105703-01 and 1UG3TR003264-01, and funding from The ALS Association.

Cedars-Sinai owns a minority stock interest in Emulate, the company that produces the study’s microfluidic Organ-Chips. An officer of Cedars-Sinai also serves on Emulate’s Board of Directors. C.N.S serves on the advisory board of Cell Stem Cell.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

May 22—and marked the occasion with a visit from NASA astronaut and microbiologist Kate Rubins, PhD.

“The Center for Space Medicine Research leverages our expertise in academics, research and clinical medicine and builds on a decade of work in the Regenerative Medicine Institute,” said Arun Sharma, PhD, associate professor of Biomedical Sciences at Cedars-Sinai and director of the new research center. “Space biomedicine is a rapidly emerging field, and we are building a solid body of research into what happens to the human body in space and how stem cells behave in microgravity.”

Cedars-Sinai has sent five experiments on missions to the International Space Station, with more planned beginning in late summer. In addition to space experiments, the new center will establish an educational initiative tied to the Cedars-Sinai Master of Science in Regenerative Medicine program, which includes space biomedicine courses, Sharma said.

“As an academic medical center engaged in disease discovery programs, Cedars-Sinai is not limiting its research to the confines of the Earth’s gravitational field,” said Shlomo Melmed, MB, ChB, executive vice president of Medicine and Health Sciences and dean of the Medical Faculty. “The establishment of this new research center is another step in our great journey of scientific discovery, translational medicine and patient care.”

Rubins, who worked with Sharma in 2016 on the first long-duration cell culture experiment in space, kicked off a seminar series devoted to space biomedicine research with a talk titled “The Next Frontier: Biomedical Research in the Second Space Age.”

Rubins earned a bachelor of science in molecular biology from the University of California, San Diego (UCSD), and a PhD in cancer biology from Stanford University Medical School’s Biochemistry, Microbiology and Immunology Departments. Throughout her two flights to the International Space Station, she spent 300 days in space and performed four spacewalks.

“We’re at the beginning of the second space age,” Rubins said. “When you lift the weight of gravity off living systems you open up exciting new pathways for discovery. Microgravity gives us physics that we just cannot buy or build on Earth.”

Rubins also stressed the potential of advances made in space to address medical and environmental issues on Earth—including sources of clean water and air and options for remote health care delivery.

Maedeh Mozneb, PhD, a project scientist in the Sharma Lab at Cedars-Sinai, has been named associate director of the center. Mozneb has been instrumental in characterizing effects of low-Earth orbit on stem cell expansion, transfection, reprogramming and differentiation. Additional faculty members include Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute, Dhruv Sareen, PhD, associate professor of Biomedical Sciences and chief biomanufacturing officer for the Cedars-Sinai Biomanufacturing Center, and Sonja Schrepfer, MD, PhD, research scientist in the Regenerative Medicine Institute.

“The Center for Space Medicine Research is the latest in a series of new projects and growth we have been pursuing on Earth and in orbit,” Svendsen said. “We are excited about this next step and look forward to new discoveries and to helping educate the next generation of space medicine researchers.”

Sharma noted that the timing—and location—are both ideal for a new space medicine endeavor. Southern California is home to the NASA Jet Propulsion Laboratory, SpaceX and enough aerospace startups in Long Beach to earn it the nickname “Space Beach.”

“People don’t always think of L.A. as an aerospace hub,” Sharma said, “but it is becoming that, and Cedars-Sinai is all in.”

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Sonja Schrepfer, MD, PhD, who recently joined the Board of Governors Regenerative Medicine Institute and the Jim and Eleanor Randall Department of Surgery at Cedars-Sinai, is a pioneer and leader in the development of “hypoimmune cells,” which are designed to thwart transplant rejection. Schrepfer authored a paper in the peer-reviewed journal Cell Stem Cell reviewing the progress and challenges in developing therapies where cells generated from one individual are transplanted to another. She sat down with the Cedars-Sinai Newsroom to discuss this emerging technology.

How did you come to study stem cells?

I started my career in medicine in 2002, caring for heart and lung transplant recipients. Seeing patients die from rejection or severe complications from immunosuppression was frustrating to me and I decided to focus my career on developing strategies to overcome immune rejection without immunosuppressive drugs. Since organs are clusters of large amounts of cells, I focused on engineering individual cells, stem cells, as a first step.

What is your approach to creating hypoimmune stem cells?

My approach uses genetic engineering to make stem cells invisible to the immune system. Nature has a mechanism for this, and pregnancy is the classic example. Half of the cellular proteins in a developing fetus are inherited from the father and are foreign to the mother. The fetal cells use hypoimmune mechanisms to prevent attack by the mother’s immune system. Studying these mechanisms led me to devise our current strategy. Over the course of more than a decade, using genome editing, I have managed to engineer stem cells that are invisible to the immune system. The advantage of engineering hypoimmune stem cells is that when these stem cells proliferate and create new cells, the new cells are also hypoimmune.

Are you the first person to create hypoimmune stem cells?

I was the first to use the hypoimmune gene edits, and it is probably fair to say that the word “hypoimmune” came from me. I was the first to publish on this topic and am thrilled to now see it used by many teams—though they use different approaches. The cells they create evade immune detection, meaning the host immune system doesn’t recognize the cells as foreign and does not attack them. Other strategies, called immune tolerance, attempt to teach the body’s immune system to accept the donor cells as their own. Right now, these concepts are classed together, but I am hoping the field will recognize that these are different concepts.

Do your hypoimmune edits only work with certain cell types?

We can use these edits on any type of cell. The advantage of creating hypoimmune stem cells is that you then have unlimited supply, because they proliferate endlessly, and they can be differentiated into any cell type.

Have hypoimmune stem cells been successfully turned into other cell types?

In my preclinical work, we turned the cells into many different cell types, including heart muscle cells; smooth muscle cells, found in blood vessel walls; and endothelial cells, which form the inner lining of blood vessels. The exciting thing about being here at Cedars-Sinai is that we have all the technology and great teams ready to take that next step and turn these cells into many more cell types on a larger scale.

What are some possible clinical uses for cells created from hypoimmune stem cells?

Hypoimmune stem cells could be used in a variety of cell therapies now being developed to treat diseases such as ALS [amyotrophic lateral sclerosis], retinitis pigmentosa, diabetes mellitus and inflammatory bowel disease. Using hypoimmune stem cells will allow production of cell therapies in great quantities and make them available to more patients. Additional research is still needed in all of these areas, but we continue making progress.

What questions are you working to answer next?

My dream is to take this concept from hypoimmune cells to hypoimmune organs and overcome the solid organ transplant barrier. We have done some initial experiments to prove the concept, but there is still a long way to go. If we can prove our method overcomes organ rejection in humans, that opens the door to addressing many different diseases. And because I began in organ transplantation, this would close the loop for me.

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“Our four pillars are scientific discovery, biomanufacturing, education and training, and clinical trials,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and professor of Medicine and Biomedical Sciences at Cedars-Sinai. “We’ve made great strides in each over the past 15 years and now look forward to continuing to build on existing programs and to developing new ones.”

To that end, Helen Goodridge, PhD, will take on a new role as associate director of the institute, John Chute, MD, will become director of the Blood Program, and Dhruv Sareen, PhD, will become the chief biomanufacturing officer for the Cedars-Sinai Biomanufacturing Center, which creates clinical-grade cell products for regenerative medicine. The institute also will launch the Master of Science in Regenerative Medicine Program under the direction of Wafa Tawackoli, PhD, the institute’s director of Education and Training.

Svendsen noted that much of the institute’s growth has been enabled by the California Institute for Regenerative Medicine (CIRM), a state agency providing funding to accelerate stem cell, regenerative medicine and gene therapy research, and the Cedars-Sinai Board of Governors, a group of philanthropic leaders who support clinical programs, biomedical research and community outreach.

Key Milestones

Key milestones since the institute was founded in 2010:

2011: The institute launches the Induced Pluripotent Stem Cell Core Facility, one of the first facilities in California dedicated to the production of induced pluripotent stem cells.

2012: Svendsen receives a $17.8 million grant from CIRM to develop a novel treatment for amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease.

2018: An institute team advances organ-on-chip technology, which combines induced pluripotent stem cells and specially engineered laboratory devices to recreate biology outside the body. This work was highlighted on the cover of National Geographic.

2019: A CIRM-funded clinical trial to study a stem cell-based treatment for retinitis pigmentosa, an inherited eye disease with no cure, enrolls its first patient.

2020: The institute opens the Regenerative Orthobiologics Center to identify stem cell-based treatments for musculoskeletal injuries or disease.

2020: The institute opens the Cedars-Sinai Biomanufacturing Center, which houses clean-room cell production suites and process development rooms for producing the next generation of cell and gene therapies.

2022: Institute investigators send experiments on the first of four missions to the International Space Station to explore the possibility of producing large batches of stem cells in a low-gravity environment.

2022: The institute launches the Cedars-Sinai Alpha Clinic, part of a statewide network of CIRM-funded clinics that conducts cell and gene therapy trials focused on disorders with unmet medical needs.

2024: Cedars-Sinai opens the CIRM Shared Resources Laboratory for Advanced Stem Cell Modeling, which serves as a hub for the development of organ-chip technology.

A New Master’s Program

The introduction of the Master of Science in Regenerative Medicine Program within Cedars-Sinai’s Health Sciences University marks yet another milestone for the institute.

“Cedars-Sinai is a leader in regenerative medicine, stem cell biology research and biomanufacturing, and we are ready to educate the next generation of young scientists to contribute to this exciting field,” said Tawackoli. “We have robust programs for high school students, PhD students and postdoctoral fellows, and a Master of Science in Regenerative Medicine Program is a logical addition to our education portfolio.”

The 20-month program will accept four to six students in its first class, pairing each student with a specific laboratory and mentor in their second year. The curriculum will focus on three professional paths: biomanufacturing, academic research and clinical specialties. Deadline to apply is June 30, 2025.

“We plan to invite biotech industry professionals to share what kind of job candidates they are looking for, so our graduates are well trained for any of these three categories and have the upper hand in their job searches,” Tawackoli said. “This will also offer good preparation for those who plan to continue their education in medical or PhD programs.”

New Leadership Roles

In her new role, Goodridge, previously associate director of Discovery at the institute, will assist Svendsen with strategic planning for the institute’s next 15 years of milestones.

“This appointment gives me an opportunity to work with Dr. Svendsen and other institute leaders to shape the vision for the next 15 years,” Goodridge said. “I have been here to see the growth within the institute and at Cedars-Sinai as a whole. It is amazing how the field has evolved and exciting to think about where we will go next. I enjoy my research, but it is great to also be part of the big picture and to have had many opportunities over the years to collaborate both in the research space and across the institution.”

Chute, director of the Division of Hematology and Cellular Therapy at Cedars-Sinai, will now also direct the Blood Program in the regenerative medicine institute.

“The Blood Program is vital to our ongoing efforts to develop next-generation cellular and immune effector therapies for patients with blood diseases, cancers and immunologic diseases,” Chute said. “We’re interested in expanding the boundaries of CAR T-cell therapy, in which a patient’s own immune cells are trained to attack cancer cells. CAR T-cells are currently used to treat blood diseases, and we are developing novel CAR T-cells to eradicate solid cancers as well as targeting neurologic, immune and pulmonary diseases. With the clinical expertise we have in the Cedars-Sinai Division of Hematology and Cellular Therapy and the resources of the regenerative medicine institute, we are rapidly accelerating translational research and product development in this area. We aim to launch clinical trials of our novel cellular therapies within the next two years.”

Sareen, founding executive director of the Cedars-Sinai Biomanufacturing Center, is being promoted to chief biomanufacturing officer, a move Svendsen said reflects the leadership he has shown in building the center from the ground up.

“As the regenerative medicine institute grew, we established the biomanufacturing center to accelerate internal pipelines for translational medicine, using innovative cell therapy and cell manufacturing platforms we have developed,” Sareen said. “Our goal is to get some of these advanced therapies into clinical trials for patients with intractable diseases such as gastrointestinal cancers, autoimmune diseases and neurological diseases like ALS.”

Going forward, Sareen said he plans to work to deepen ties across academia, industry and government agencies to build a robust ecosystem to provide cell and gene therapies to the Los Angeles community and beyond.

“Over the past 15 years, Dr. Svendsen has developed a leading-edge institute that has attracted clinicians and scientists across all departments to Cedars-Sinai and created a unique environment for the growth of innovative stem cell treatments for our patient community,” said Shlomo Melmed, MB, ChB, executive vice president of Medicine and Health Sciences and dean of the Medical Faculty at Cedars-Sinai. “We anticipate great things during the institute’s next 15 years.”

Svendsen is also looking toward the future.

“Regenerative medicine is an emerging field and the future possibilities for using stem cells to both model and treat human disease here at Cedars-Sinai are endless,” he said. “I will devote my efforts to moving all this exciting research into clinical trials that we hope will bring new treatments to patients within our community and beyond and help fulfill the founding mission of Cedars-Sinai.”

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“One of the most challenging tumors to treat is cancer that has spread to the brain,” said Lali Medina-Kauwe, PhD, associate director of Basic Research at Cedars-Sinai Cancer, professor of Biomedical Sciences, and senior author of the study. “Our findings show that our tumor-invading protein can deliver a potent payload of therapy directly to these tumors. It is like a cancer smart bomb.”

A challenge in delivering chemotherapy to brain tumors has been the blood-brain barrier, which stops harmful particles from traveling from the bloodstream to the brain but also blocks therapeutic agents. Medina-Kauwe and team found that a protein called HER3 is present on the blood-brain barrier, and that it helps their tumor-invading protein cross from the bloodstream to the brain.

The investigators conducted experiments using a unique blood-brain barrier “organ chip.” In this laboratory device, small groups of induced pluripotent stem cells are transformed into blood vessel cells and brain cells and put in compartments in a pattern that mimics what happens in the human brain.

When investigators flowed their protein through the blood vessel portion of the chip, they saw that it crossed over and accumulated in the brain matter, Medina-Kauwe said. And when they blocked HER3 proteins in the chip, tumor-invading proteins did not cross over, which suggests that HER3 aids their passage from the bloodstream into the brain.

“These blood-brain barrier organ chips are the next best thing to experiments in humans,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and a co-author of the study. “They allow us to create the ideal conditions for testing therapies such as this one. We can even use the patient’s own stem cells and make personalized organ chips to test how the drug may work for each person.”

The HER3 protein is also present on the surface of many types of cancer cells—especially in tumors that have spread from another part of the body to the brain. And the investigators’ experiments in laboratory mice showed that tumor-invading proteins directly targeted these HER3-positive tumors, reducing their growth without accumulating in other organs.

“Most cancer drugs enter healthy cells as well as cancerous cells, causing major side effects, but this tumor-invading protein selectively enters tumor cells and spares the healthy cells,” said study co-author Ravinder Abrol, PhD, associate professor of Chemistry and Biochemistry at California State University, Northridge (CSUN), and member of the Cancer Biology Program at Cedars-Sinai. “Our ability to actively target tumor cells is a major step toward cancer therapies with reduced toxicity and enhanced safety profiles.”

Once the protein enters tumor cells, a unique feature allows it to evade their defenses.

“Most cells, including tumor cells, encapsulate invading particles in a bubble that allows the cell to harmlessly digest them,” Medina-Kauwe said. “Our tumor-invading protein includes a pinwheel-like structure that prevents digestion. When our protein enters the unique environment of the tumor cell, it opens this pinwheel and breaks out of the bubble. When we pair the protein with chemotherapy, it can deliver a lethal blow.”  

Medina-Kauwe said the findings are promising and are a step toward developing therapies that can deliver treatment to advanced tumors that currently have no other clinical option.

“We are finding that more and more tumor types—including breast, lung and colorectal tumors, and metastatic melanoma, as well as many primary brain tumors—are HER3 positive,” Medina-Kauwe said. “We’re looking forward to pursuing further studies to determine whether we can develop treatments for these tumor types.”

Additional Cedars-Sinai Authors: Felix Alonso-Valenteen, Simoun Mikhael, HongQiang Wang, Jessica Sims, Michael Taguiam, James Teh, Sam Sances, Michelle Wong, Tianxin Miao, Dustin Srinivas, Nelyda Gonzalez-Almeyda, Ryan H. Cho, Kimngan Nguyenle, Erik Serrano, Briana Ondatje, Rebecca L. Benhaghnazar, John Yu, Clive N. Svendsen, Ravinder Abrol

Additional Authors: Romny Sanchez, Harry B. Gray, Zeev Gross

Funding: This research was supported by grants from the National Institutes of Health (NIH) [NCI R01 CA258204, R01 CA270324, and NCATS UL1 TR001881 core vouchers V002, V087, and V176 to L.M.K]; and the Department of Defense (DoD) [BCRP W81XWH-15-1-0604, W81XWH1910592 to L.M.K and R.A.]. F.A.V. was supported in part by a training grant from the National Institutes of Health [T32 HL134637]. B.O. and S.S. were supported by National Institutes of Health (NIH) UG3NS105703.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

By introducing DNA into mature adult cells, scientists can reprogram them into a type of stem cell called induced pluripotent stem cells. They can then turn the cells into other cell types. This process has been used for years to manufacture or replicate large numbers of cells for research and the development of new disease treatments.

Previous studies have found that when grown under microgravity, the near-weightlessness found in space, stem cells function differently. The lack of gravity could speed up cell manufacturing, said Arun Sharma, PhD, research scientist in the Cedars-Sinai Board of Governors Regenerative Medicine Institute, research professor in the Department of Biomedical Sciences and the Smidt Heart Institute and co-senior author of the study.

“Our goal has been to understand and harness those differences to more effectively and efficiently produce stem cells in a way that’s impossible on Earth,” Sharma said. “Cedars-Sinai is now the first to successfully introduce DNA into human induced pluripotent stem cells in space, establishing the foundation for our next step toward large-scale manufacturing of stem cells in space.”

The experiments took place aboard Axiom Mission 2, Axiom Space’s second astronaut mission to the International Space Station.

“We are pleased to be partnering with the Cedars-Sinai team on this NASA-funded in-space manufacturing program, leveraging microgravity to establish production of stem cell therapies,” said Pinar Mesci, PhD, global head of Regenerative Medicine & Disease Modeling at Axiom Space. “This publication is an important step toward demonstration of how human pluripotent stem cells can be cultured, transfected and grown in low-Earth orbit using commercial, off-the-shelf terrestrial hardware that will accelerate research and discovery as well as in-space manufacturing.”

During the mission, cells that had been frozen for transport were thawed and transferred into cell culture dishes by specially trained astronauts. Among them was Rayyanah Barnawi of the Saudi Space Agency, the first Saudi and female astronaut, first Arab woman in space, and a co-author of the study. 

“Among the technical challenges associated with doing this kind of work in space was the challenge of keeping the cells in their dishes,” Sharma said. “On Earth, if we want to change the nutrients in a dish, we simply open the lid. In microgravity, if you open a lid, everything will escape. On this mission, we discovered that the surface tension of the fluid in 96-well plates commonly used in labs was enough to hold the cells in place in microgravity, meaning we didn’t need custom equipment for these experiments.” 

Investigators on Earth, including lead study author and project scientist Maedeh Mozneb, PhD, performed identical experiments so that the two sets of cells could be compared. One surprise from space: The cells arranged themselves into three-dimensional spheres, rather than lying flat in a dish as they would on Earth.

“That was a very exciting surprise,” Sharma said. “We weren’t intending to grow the cells in three dimensions. The cells did that on their own. This makes sense, because in the microgravity found in space, things float around, and the cells floated and arranged themselves into spheres.”

This has made investigators think about the next step in the process of stem cell manufacturing, and how this new discovery might be used. 

“We’ve since completed additional missions directed at making human induced pluripotent stem cells entirely in microgravity,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute, professor of Medicine and Biomedical Sciences at Cedars-Sinai, and co-senior author of the study. “These studies are ongoing and we hope will ultimately advance stem cell technology by providing a unique type of stem cell—one made in space.”

Additional Cedars-Sinai Authors: Madelyn Arzt, Stephany Pohlman, George Lawless

Additional Authors: Pinar Mesci, Dylan MN Martin, Shankini Doraisingam, Sultan Al Neyadi, Rayyanah Barnawi, Ali Al Qarni, Peggy A. Whitson, John Shoffner, Jana Stoudemire, Stefanie Countryman 

Funding: A.S. and C.N.S. are supported by the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and an In-Space Production Award (InSPA) from NASA (NNJ13ZBG001N). A.S. received support from the American Heart Association Career Development Award 856987.  

Read more in Discoveries: Frontiers in Single-Cell Biology

, hosted by Cedars-Sinai on Oct. 25.

“This meeting isn’t just for scientists,” said Michael I. Lewis, MD, program director of The Alpha Clinic at Cedars-Sinai and professor of Medicine. “It is for clinicians, patients and members of the public who are interested in learning more about cell and gene therapies, emerging technologies, innovative clinical trial designs and issues surrounding accessibility to these therapies for patients, such as financial barriers.”  

The symposium, sponsored by the California Institute for Regenerative Medicine (CIRM), will take place from 9 a.m.-5 p.m. at the Cedars-Sinai Silver Screen Theater in the Pacific Design Center. Virtual registration is also available.

Scientists from all nine California Alpha Clinics are set to speak. Along with Cedars-Sinai, institutions with alpha clinics include University of California, San Diego; University of California, Los Angeles; University of Southern California and Children’s Hospital Los Angeles; Stanford University; University of California, Irvine; University of California, Davis; City of Hope; and University of California, San Francisco.

Directors of several Alpha Clinics will moderate panel discussions, and directors of the Alpha Clinics at UC Irvine, UC San Diego, University of Southern California and UC Davis will participate in a discussion of Alpha Clinic operations. Daniela A. Bota, MD, PhD, director of the UC Irvine Alpha Clinic, will talk about chimeric antigen receptor (CAR) therapies, and Mark Walters, MD, UC San Francisco Alpha Clinic director, will discuss current gene therapies, future opportunities and barriers to treatment. 

Lewis expects speakers to highlight the importance of diversity in clinical trials, promote collaboration among researchers and showcase advances in cell and gene therapies.

“The symposium will look to the current status of the field and, more importantly, to the future, as new approaches and therapies are likely to rapidly expand,” said Clive Svendsen, PhD, co-associate project director of Cedars-Sinai's Alpha Clinic and executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai. Svendsen recently co-authored a review paper published in Nature Medicine about stem cell-based therapies for neurological conditions.

The review paper describes stem cell-based treatments for a number of neurological disorders, including amyotrophic lateral sclerosis, also known as ALS. The condition affects nerve cells in the brain and spinal cord that control movement. ALS eventually causes loss of the ability to move, speak, eat and breathe. At this time there is no cure.

The Cedars-Sinai Alpha Clinic is conducting a trial of a therapy, developed by Svendsen and his team, using specially engineered cells to protect damaged motor neurons. To date, six patients have been treated, with no major complications.

Cedars-Sinai’s Alpha Clinic and others throughout California are developing stem-cell based therapies for a variety of conditions: 

• Cedars-Sinai is studying a therapy for retinitis pigmentosa, which breaks down cells in the light-sensitive layer at the back of the eye, the retina, leading to vision loss. The therapeutic cells in the trial release proteins that help protect retinal cells from damage.
• Cedars-Sinai investigators also are testing a treatment for pulmonary arterial hypertension, a rare condition in which elevated blood pressure in lung blood vessels can damage the heart. The initial study was led by Lewis, director of Respiratory Care Services at Cedars-Sinai, and Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and associate project director of The Alpha Clinic. Investigators concluded that infusions of specialized cell products derived from heart tissue seemed to improve patients’ heart and lung health.
• Alpha Clinics throughout California are studying stem cell-based therapies for several other conditions—including movement disorders such as Parkinson’s disease and Huntington’s disease; Alzheimer’s disease; stroke; epilepsy; spinal cord injury; and multiple sclerosis.

“The Alpha Clinic network is dedicated to accelerating the work of institutions in California, such as Cedars-Sinai, that are developing and testing cell and gene therapies,” Marbán said. “It is a highly collaborative group, and we share resources including our expertise, our infrastructure and our experience with cell delivery to help each other.”

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is creating a resource laboratory to help advance stem cell-based technologies throughout Cedars-Sinai and across California. The institute will serve as a hub for the development of organ-on-a-chip and organoid models that bring precision to patient care and research.  

“We’ve developed extensive expertise in creating induced pluripotent stem cells from patients, then turning those into models of the liver, kidney, heart, lung, brain, spine, pituitary gland, pancreas and other organs,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and professor of Biomedical Sciences and Medicine at Cedars-Sinai. “We’re now going to provide a core resource so that investigators across Cedars-Sinai and beyond can learn to use these technologies.”

The Cedars-Sinai Shared Resources Laboratory for Advanced Stem Cell Modeling is funded through a $4 million infrastructure grant from the California Institute for Regenerative Medicine (CIRM). The lab will be available to scientists throughout California.

“The Cedars-Sinai Shared Resources Laboratory will be part of a collaborative network of 11 such laboratories across California,” said Uta Grieshammer, CIRM SRL Program lead. “We are looking forward to supporting this network of labs as they share their expertise and provide access to cutting edge technologies, with the goal of accelerating discoveries in regenerative medicine and growing and diversifying the cohort of stem cell researchers in the state.”

Induced pluripotent stem cells, or iPSCs, are cells that can be turned into many different cell types. These cells, in turn, can be grown on specialized chips that allow them to function the way they would in organs in the body. The cells also can be developed into organoids, which are miniaturized, simplified cell groups that mimic some of the key functions of organs.

In recent years, Cedars-Sinai investigators have used organoids and organ-chip technology to study gastrointestinal disease, neurological disorders, Crohn’s disease, musculoskeletal disorders, pituitary tumors, liver diseases, ovarian and breast cancer, lung fibrosis, the cardiotoxicity of cancer therapies, and how cancer develops.

“IPSC-derived organoids hold tremendous promise as a way to further our understanding of cancer development and progression,” said Joshua Breunig, PhD, director of the Cell, Organoid, and Cancer Engineering Special Resource in the Board of Governors Regenerative Medicine Institute. “We can collect a patient’s normal cells, engineer them to become iPSCs and pair the resulting organoids with genetically engineered self-renewing tumors, allowing us to discover and test therapeutics in a more natural tissue-like context.”

In this way, the organoids can truly “personalize” disease models, Breunig said.

“This new resource will give researchers throughout California access to this exciting and powerful new technology,” said Arun Sharma, PhD, research scientist in the Board of Governors Regenerative Medicine Institute and the Smidt Heart Institute at Cedars-Sinai and project director of the new laboratory. “Several of our faculty are highly experienced in this area of research and we will provide outstanding training to others through our educational programs. This includes trainees from underrepresented groups who otherwise might not have access to these systems.”

Cedars-Sinai has received several previous grants from CIRM, including grants for training of graduate and postdoctoral students, grants to develop stem cell-based disease treatments, and grants for biomanufacturing of induced pluripotent stem cells.

“We have developed nearly 1,200 iPSC lines—from healthy patients as well as those with ALS [amyotrophic lateral sclerosis], Parkinson’s disease, Alzheimer’s disease, inflammatory bowel disease, pancreatic cancer and other conditions,” said Dhruv Sareen, PhD, founding executive director of the Cedars-Sinai Biomanufacturing Center and the iPSC Core. “We are putting these into organ-chip models to help us understand disease characteristics and discover new treatments. This new lab will help us—and scientists throughout California—make progress to benefit patients everywhere.”

Read more from Discoveries: Gut Check

“We will be conducting the entire induced pluripotent stem cell reprogramming process in space, and this is the first time this has been done,” said Arun Sharma, PhD, a stem cell biologist and research scientist with the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

Induced pluripotent stem cells, or iPSCs, are adult cells that are reprogrammed into a state where they can be turned into many other cell types. Large volumes of iPSCs are needed for research and to create stem-cell-based treatments for disease, and investigators believe that the microgravity environment of space could make it easier to manufacture the cells.

During the mission, funded through a NASA In Space Production Applications Award, astronauts aboard the International Space Station will work with cells supplied by the Allen Institute for Cell Science. They will add the elements that will reprogram the cells into stem cells, and periodically transfer the cells to an imaging system that allows investigators on Earth to check on their development.

“Reprogramming the cells is the first step in the iPSC manufacturing process,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute. “The next stage is expansion, which is the growth and replication of the cells so that we can produce billions of them. We want to know how microgravity affects these processes.”

Lessons learned in space will help determine whether large-scale stem cell manufacturing there is feasible, and also will inform biomanufacturing of stem cells on Earth, Svendsen said.

“This space mission will test stem cell manufacturing on a small scale,” said Dhruv Sareen, PhD, founding director of the Cedars-Sinai Biomanufacturing Center and the iPSC Core Facility. “We will use what we learn through these experiments, and lessons from our previous experiments with automated processes in space, to determine how to scale up and create best manufacturing practices for these cells.”

The astronauts will employ the same reprogramming technique developed and used at Cedars-Sinai.

After approximately one month, preserved samples of the cells from the mission will be returned to Earth for quality testing. If all goes well, a mission planned for next year will see the cells turned into brain and heart cells, Sharma said.

“On Earth, we have challenges growing iPSCs, but what if they grow beautifully in microgravity?” Svendsen said. “And what if cell lines created in space have unique characteristics? These are the big questions. And if in 20 years we're making stem cells in space, these experiments will be the origins of it.”

Cedars-Sinai partners in the mission include Axiom Space and BioServe Space Technologies. Project scientist Maedeh Mozneb, PhD, and research associate Madelyn Arzt are key members of the team from the Sharma Lab.

The mission will launch from NASA’s Kennedy Space Center in Florida, on a Northrop Grumman Cygnus spacecraft perched atop a SpaceX Falcon 9 rocket.

The launch is part of a series of NASA-funded missions in which Sharma, Svendsen and Sareen have played key roles. Sharma has also recently been awarded an International Space Station National Laboratory Igniting Innovation grant to conduct further stem cell experiments in space.

“This grant will build on our existing research into biomanufacturing in space with two additional missions,” Sharma said.

The first mission will focus on the creation of cardiac spheroids in space. Cardiac spheroids are tiny clumps of heart muscle cells and heart blood vessel cells, created from stem cells, that function much the way they do in an actual human heart.

“We want to see if the microgravity environment can facilitate the creation of these spheroids,” Sharma said. “It’s possible we’ll be able to achieve better symmetry in space than we can on Earth, where gravity compresses the spheroids against the dish.”

Following that mission, a second mission, connected to the White House Cancer Moonshot, will involve the use of these spheroids to test the potential heart damage (cardiotoxicity) caused by cancer drugs.

“My lab has conducted experiments using stem cell-derived heart cells to explain why and how cancer drugs can damage the heart,” Sharma said. “We’re hoping that these spheroids, created in space, will give us a better way to screen cancer drugs for cardiotoxicity.”

Learn more on the Cedars-Sinai Blog: Stem Cells in Space

and professor of Medicine and Biomedical Sciences at Cedars-Sinai, is developing new treatments and models for amyotrophic lateral sclerosis (ALS) using stem cells.

ALS progressively destroys nerve cells in the brain and spinal cord, causing people to lose muscle movement required for walking, talking, swallowing and breathing. Currently, the disease is irreversible and has no cure, but a potential therapy that combines gene and stem cell technologies is progressing well, according to Svendsen.

Svendsen has been selected as an inaugural recipient of a grant from the Tambourine ALS Breakthrough Research Fund, funded by Tambourine and administered in partnership with the Milken Institute. The grant will fund research that combines advanced stem cell modeling with artificial intelligence to learn more about the cause of ALS. Svendsen sat down with the Cedars-Sinai Newsroom to discuss his ALS research and new projects that the grant will help fund.

What is unique about the ALS therapy you are developing?

It uses a protein called GDNF (glial cell line-derived neurotrophic factor), which is a nutrient that brain cells can use to mature and survive. It promotes the growth of axons, the threadlike structures brain cells use to communicate, and also helps damaged cells rejuvenate.  

In ALS, motor neurons are dying. And there is evidence that GDNF can help protect them. The problem is that GDNF is a large protein and it cannot pass through the barrier that protects the brain by preventing potentially harmful substances from entering it.

So how do you get GDNF into the brain and spinal cord?

We've developed a clever technique, like a Trojan horse. We've engineered a human stem cell called a neural progenitor to release GDNF, and we're transplanting those cells into the spinal cords and brains of patients with ALS. The idea is that the progenitor cells mature into healthy support cells and release GDNF that will help heal diseased motor neurons. 

How are clinical trials of the therapy going?

Our first trials are to ensure the therapy is safe for patients. We have completed a Phase I/IIa clinical trial to treat the lower motor neuron, which controls leg movement, in 18 patients with ALS. We had good safety data in every one of those patients. Those results were published in Nature Medicine.

We only put the cells on one side of each patient’s spinal cord, so we could compare the treated leg to the nontreated leg. While the focus of this initial study was safety, we did see a trend toward improvement in the treated limb after 12 months, even though the patients were at an advanced disease stage. We plan to perform an additional trial with patients who are earlier in the disease process and with optimized cell targeting, and hope to significantly improve limb function.

As the upper motor neuron in the brain is also affected in ALS, we’ve started an additional safety trial where we will treat the upper motor neurons, specifically those that control hand movement.  We've treated five patients and the trial is still open. Our next step will be to treat both the upper and lower motor neurons, and at that point, we will also measure the effectiveness of the therapy. If our technique is working, we should see a slowing of disease progression in the treated hand and leg. Research Project Advisor Pablo Avalos, MD; Adam Mamelak, MD, director of the Functional Neurosurgery Program at Cedars-Sinai; and Richard Lewis, MD, director of the Electromyography Laboratory at Cedars-Sinai, are key contributors to this work.

What will the Tambourine grant fund?

With the help of the Cedars-Sinai Biomanufacturing Center, as part of a large consortium called Answer ALS, we have generated induced pluripotent stem cells from 1,000 patients with ALS. We have full clinical records and genomic sequencing for these patients. Induced pluripotent stem cells are adult human cells taken back in time to a stage where they are capable of developing into any cell in the body. We’re then differentiating those cells into motor neurons that are known to die in ALS patients.

In collaboration with MIT [Massachusetts Institute of Technology], we will use the Tambourine grant to fund an advanced imaging project, called cell painting, on these motor neurons. Michael Workman, a project scientist in my laboratory, has been a key contributor to these studies. Up to six fluorescent dyes are used to label different components of the cells. With the help of an advanced, high-powered microscope and massive cloud computing, each individual neuron will be analyzed. 

We will use artificial intelligence to attempt to distinguish ALS patients from healthy patients, and then look for molecular “signatures” within ALS patients that define subgroups. This data can be used to develop new targeted drugs to treat specific subgroups of ALS—a truly personalized medicine approach leveraging the latest medical technology. This could be a big boost for clinical trials and drug development.

Read more on the Cedars-Sinai Blog: Regenerative Medicine: A New Path for ALS Treatment

“The key to this discovery was our ability to directly compare injured kidney cells that successfully regenerated with those that did not,” said Sanjeev Kumar, MD, PhD, a nephrologist-scientist in the Board of Governors Regenerative Medicine Institute and the Department of Medicine at Cedars-Sinai and senior author of the study. “Injured cells activate a protein called SOX9 to regenerate themselves. When they have healed, the cells silence this protein. Cells that aren’t able to regenerate leave SOX9 active, and this leads to a type of scarring called fibrosis. But when we deactivate SOX9 in a timely fashion, the scarring literally goes away.”

The kidneys, two fist-sized organs that filter waste from the blood, can be injured by diabetes and high blood pressure, serious infections such as COVID-19, and overuse of antibiotics and non-steroidal anti-inflammatory pain medications, said Kumar, who is also part of the Department of Biomedical Sciences at Cedars-Sinai. 

The SOX9 protein plays a major role in organ development but is not active in healthy adult kidneys. In previous work at another institution, Kumar and team found that when kidneys are injured, the surviving cells reactivate SOX9 as part of the healing process.

In this study, Kumar and fellow investigators studied kidney damage in laboratory mice. They labeled individual cells at the point of injury, then followed how the cells’ progeny evolved over time.

“At Day 10, some cells’ descendants were fully healed while others were not,” Kumar said. “The cell lineage that healed had switched off SOX9 expression, while the unhealed lineage, in a continuing attempt to fully regenerate, maintained SOX9 activity. It’s like a sensor that switches on when cells want to regenerate, and off when they are restored, and we are the first to identify this.” 

Further, investigators discovered that cells that were unable to regenerate began recruiting proteins called Wnts, another key player in organ development. Over time, this accumulation of Wnts triggered scarring. And they found that deactivating SOX9 a week after injury promoted kidney recovery.

Investigators observed the same process in patient databases from collaborating institutions in Switzerland and Belgium.

“We could see that by Day 7, human patients with transplanted kidneys that were slow to begin working also activated SOX9,” Kumar said. “And in our collaborators’ database, we were able to distinguish that patients who had sustained SOX9 activation had lower kidney function and more scarring than those who did not. Human kidneys with cells that maintained SOX9 were also enriched with Wnts and showed increased fibrosis.”

These discoveries provide targets for drug development, as well as for noninvasive biomarker discovery permitting diagnosis of kidney fibrosis through the urine, Kumar said. Currently, the only available test for kidney fibrosis is a biopsy, which carries many risks.

“Elucidating the mechanisms of scarless healing versus fibrosis has eluded investigators for decades and has implications beyond the kidney, including for certain cancers,” said Paul Noble, MD, chair of the Department of Medicine and director of the Women’s Guild Lung Institute at Cedars-Sinai and a co-author of the study.

The findings could also lead to new treatment options for patients, said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and a co-author of the study.

“These findings help us understand for the first time how the kidney’s response to injury sometimes leads to fibrosis,” Svendsen said. “Future work along these lines could also advance our understanding of fibrosis in the heart, lungs and liver.” 

Funding: This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health grant number R01 DK118265, American Heart Association award number 18CDA34110416, a John Merrill Transplant Scholar Grant from the American Society of Nephrology, a UCLA CTSI Catalyst Award, a One Legacy Foundation grant, Department of Defense grant numbers DoD CDMRP and KC200178, Swiss National Foundation grant number Sinergia CRSII5_202302, and by the Balli and Gianella foundations.

Read more on the Cedars-Sinai Blog: A New Kidney in the Nick of Time

they show that the heart-on-a-chip, created using stem cells, accurately predicts the effects of drugs on human heart cells.

The investigators worked with induced pluripotent stem cells, which are blood cells that have been reprogrammed into stem cells and can be turned into any cell type in the body. They used the stem cells to create two types of heart cells, but instead of placing them all together in an unstructured cell culture dish, as is usually done in heart toxicity testing, the investigators introduced the cells into specialized chips.

The 3D chips feature two channels that are arranged to cross each other, keeping each cell type separate but allowing them to interact. The chips also allow for movement and the introduction of fluids.

“We grew heart muscle cells and blood vessel cells,” said Arun Sharma, PhD, a research scientist in the Board of Governors Regenerative Medicine Institute, Smidt Heart Institute, Cedars-Sinai Cancer, and the Department of Biomedical Sciences at Cedars-Sinai and senior author of the study. “The chip allows us to stretch the cells back and forth to mimic a heartbeat, and to introduce fluid to mimic the flow of blood through the heart. It’s like giving the cells a workout that strengthens the muscle cells and allows the vessel cells to form mini blood vessel-like structures.”

These “matured” cells provide a better test platform for drug toxicity studies than cells that haven’t undergone this maturation process because they more closely resemble the way adult heart cells function, Sharma said.

To demonstrate the proficiency of heart-on-a-chip as a drug-testing platform, the research team, including lead author and postdoctoral fellow Maedeh Mozneb, PhD, subjected the heart chip to a chemotherapy drug called a VEGFR/PDGFR-inhibiting tyrosine kinase inhibitor, which is known to have adverse effects on heart muscle and blood vessel cells. Damage was observed to both cell types in the heart chips.

If future studies continue to show good results, heart-on-a-chip technology could significantly reduce drug development costs and improve the rate at which new therapies become available.

Another future possibility for these heart chips is the creation of patient-specific chips to personalize cancer treatment.

“If a patient with cancer might receive a treatment that could have adverse effects on their heart, we can create induced pluripotent stem cells from a small sample of their blood,” Sharma said. “We can turn those stem cells into heart muscle and blood vessel cells and put them on a chip that will serve as a personalized avatar for how that person’s heart might react to the treatment. This is one of the most exciting applications of this technology, truly advancing personalized medicine at Cedars-Sinai.”

Also a possibility: Taking these chips beyond a single organ.

“We eventually hope to bring our various organ models together,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and co-author of the study. “My lab has been fine-tuning this technology to help us develop models of neurological diseases, and other labs in our institute have been working on chips for the liver and the gut microbiome. Bringing all of these chips together to create a ‘patient-on-a-chip’ model is part of our long-term vision for precision medicine.”

Funding: This project was supported by American Heart Association Career Development Award 856987; National Institutes of Health grant numbers T32 HL116273, 1UG3TR003148, and 5UG3NS105703; Allen Distinguished Investigator Award number 12879; the Cedars-Sinai Board of Governors Regenerative Medicine Institute; and The ALS Association.

Read More from Discoveries: Regenerative Medicine—A New Path for ALS Treatment

The Phase I clinical trial results are published in the peer-reviewed journal eBioMedicine, a Lancet journal.

“Although several drugs are approved for pulmonary arterial hypertension, mortality remains high,” said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute at Cedars-Sinai, the Mark S. Siegel Family Foundation Distinguished Professor and senior author of the study. “We tried a fundamentally different approach—cell therapy delivered into the pulmonary artery—and found encouraging results, in patients already on combination conventional therapy." 

Pulmonary arterial hypertension is a rare disease, affecting fewer than 100 people per million. There currently is no cure and the average median life expectancy on treatment for most patients is roughly 6.2 years after diagnosis.

Currently approved medications for the condition aim to open up blood vessels in the lungs, allowing for better blood flow; however, studies on lungs in patients on treatment still show severe occlusive vessel changes. Further, these medications don’t address many of the complex underlying mechanisms that cause the high pulmonary pressures. Even on medication, people with pulmonary arterial hypertension can develop severe dysfunction in the right ventricle of the heart, the part that pumps blood to the lungs and whose function correlates best with survival.

Cedars-Sinai investigators are experimenting with using cardiosphere-derived cells (CDCs) to address some of the biological processes involved in pulmonary arterial hypertension. CDCs were first developed and characterized by Marbán. They have been used in multiple clinical trials for a variety of diseases, most recently, Duchenne muscular dystrophy. These are cells derived from human heart tissue that Marbán and colleagues have discovered reduce inflammation in the body and exert beneficial effects on the immune system.

Called the ALPHA study, this clinical trial was conducted in two phases. In the first, six people with pulmonary arterial hypertension received an infusion of CDCs into their lungs. Three patients received an infusion of 50 million CDCs and the other three received an infusion of 100 million CDCs.

In the second phase, 10 people with pulmonary arterial hypertension were randomized to receive an infusion of 100 million CDCs and 10 people were randomized to receive infusions containing a placebo. Investigators performed right heart catheterization and cardiac MR imaging on each study participant before the infusions and four months after the infusions.

All the participants were on combination pulmonary arterial hypertension-specific medications throughout the course of the study.

The investigators tracked the health of participants for 12 months after the infusions. No adverse effects related to the infusions occurred during this time. Although this study was only designed to assess the safety of the CDC infusions, the investigators observed encouraging changes that might indicate the 16 people who had received the CDC infusions had improved cardiopulmonary health. People who received the infusions, for example, showed improved functioning in the heart’s right ventricle and, at two months post-infusion, were able to walk a greater distance during a six-minute test than people who received placebo.

“The most important takeaway is that this approach is safe and feasible to do in people with pulmonary arterial hypertension,” said Michael I. Lewis, MD, director of Respiratory Care Services at Cedars-Sinai, and first and corresponding author of the study. “These are encouraging exploratory findings that motivate moving on to more advanced studies.”

The investigators plan additional trials to study the effects of repeated infusions of CDCs given to people with pulmonary arterial hypertension.

Cedars-Sinai investigators Mamoo Nakamura, MD; Dael Geft, MD; Yuri Matusov, MD; James Mirocha; Antoine Hage, MD; Victor Tapson, MD; Oleg A. Karpov, PhD; and Jennifer Van Eyk, PhD, also worked on the study.

Funding: The study was funded by the California Institute for Regenerative Medicine (CIRM), one of the world’s largest institutions dedicated to three key areas of regenerative medicine—research, education and patient access.

Read more on the Cedars-Sinai Blog: Pulmonary Hypertension: A Patient’s Advice

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Almost 40% of the adult population experiences low back pain due to degenerating disks in the spine, but medical science hasn’t understood exactly why the disks become painful. In a new study published in the journal Science Translational Medicine, Cedars-Sinai investigators point the way to an answer—and possibly a step toward targeted treatment.

“We’ve identified for the first time particular cells that could be the key to understanding disk pain,” said Dmitriy Sheyn, PhD, research scientist in the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and senior author of the study. “Learning more about how these cells work could lead to the eventual discovery of new treatment options.”

The bones making up the spine are interspersed with jelly-filled spacers, known as intervertebral disks, that act as shock absorbers. Due to age, overuse or injury, the jelly starts to dry out and degenerate, but this doesn’t mean that the disk necessarily becomes painful, Sheyn said.

“This is because the inner jelly-like layers of the disks contain no nerve endings,” said Sheyn, who is also an assistant professor of Orthopaedics, Surgery, and Biomedical Sciences at Cedars-Sinai. “But sometimes, when disks degenerate, nerve endings from the surrounding tissues invade the disk, and we believe this causes pain.”

Several cell types exist in this jelly-like layer, and when investigators compared cells from patients with pain-free degenerated disks and patients with disk-associated low back pain, they found that patients experiencing low back pain had greater numbers of a certain subtype of cell that might be involved in the onset of the pain.

“This represents a breakthrough in our understanding of disk-associated back pain,” said Hyun Bae, MD, professor of Surgery and Orthopaedics at Cedars-Sinai and a co-author of the study. “It is an essential step toward finding a nonsurgical biologic treatment.”

“Unveiling the key cells behind disk-related pain marks a pivotal stride in reshaping how we approach back pain management,” said Mark Vrahas, MD, chair of Cedars-Sinai Orthopaedics. “This discovery opens doors to targeted therapies that may revolutionize orthopaedic treatments, offering hope to millions worldwide.”

In a cell culture dish, investigators subjected healthy cells to conditions that simulated disk degeneration—including inflammation, acidity, tension and compression, low glucose, and low oxygen—and were able to transform them into the pain-associated subtype.

Investigators also grew cells in one chamber of a special two-chamber laboratory chip. Into the other chamber, they introduced pain-signaling neurons that they had created from stem cells.

When pain-associated cells were in the chip, pain-signaling neurons in the other chamber grew axons—special fibers nerves use to send information—toward them. When healthy cells were in the chamber, the neurons didn’t send out axons.

“We don't know whether the pain-associated cells attracted the invasion of the neurons, or the healthy cells repelled it, but there was definitely a difference between the healthy and the pain-associated cells,” Sheyn said.

Future treatments based on this new information might focus on reprogramming pain-associated intervertebral disk cells into healthy cells, or on adding healthy cells to painful disks to overwhelm the pain-associated cells, according to Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

“Precisely targeting the ‘bad’ cell subtype or supplementing the ‘good’ cell subtype may provide useful strategies for treating disk-based low back pain,” Svendsen said. “This study validated some knowledge in classical disk or pain biology and could be a step toward a targeted cell therapy that addresses the root causes of low back pain.”

Additional study authors included Wensen Jiang, PhD, and Juliane Glaeser, PhD, who are both research scientists at Cedars-Sinai.

Funding: The study was funded by the Cedars-Sinai Board of Governors Regenerative Medicine Institute; National Institutes of Health grants K01AR071512, and R34NS126032; and California Institute for Regenerative Medicine grant EDUC4-12751.

Learn more on the Cedars-Sinai Blog: Treating Back Pain Without Surgery

Their preclinical animal studies were published in two peer-reviewed journals: the Journal of Translational Medicine and Stem Cells Translational Medicine.

“The first study presents a path from laboratory discovery to patients,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and co-senior author of both studies. “And in the second, we showed that engineering the cells to release a powerful growth factor enhances their protective effect on retinal cells. This supports our previous studies where the same cells have shown promise as a therapy for neurodegenerative diseases,” said Svendsen, who also holds the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine at Cedars-Sinai.

In the study in Journal of Translational Medicine, investigators injected five different doses of neural progenitor cells—cells that give rise to various neural cell types—into the retinas of laboratory rats with retinal cell and vision loss similar to humans with retinitis pigmentosa. The condition causes the degeneration of the retina—the light sensitive layer at the back of the eye—resulting in vision loss and ultimately blindness.

The study showed that the animals’ ability to respond to light stimulation was significantly preserved six months after cell treatment, compared with untreated animals. In areas where the grafted cells were distributed, photoreceptor cells, which convert light into signals sent to the brain, were preserved. Part of the study’s purpose was to evaluate any risks related to the therapy, and the results suggested that the therapy could safely be used in clinical trials in human patients.

To determine the best method for delivering the cells in human clinical trials, investigators tested surgical methods for transplanting the cells into the retinas of laboratory minipigs, which have eyes of comparable size to the human eye. Ophthalmologist David Liao, MD, from the Retina-Vitreous Associates Medical Group in Beverly Hills, and Pablo Avalos, MD, associate director of Translational Medicine at Cedars-Sinai, performed the procedures and determined which automatic injection system yielded the best outcomes.

In the study published in Stem Cells Translational Medicine, investigators addressed disease stage.

“One reason results from other animal studies have not been replicated in clinical trials is that the studies were conducted in animal models at very early stages of disease,” said Shaomei Wang, MD, PhD, a professor of Biomedical Sciences and a research scientist in the Board of Governors Regenerative Medicine Institute at Cedars-Sinai as well as a co-senior author of both papers. “Human patients are generally recruited for clinical trials at much later stages of the disease, and it is important to test stem cell therapy at a disease stage that is relevant to these patients.”

To determine whether their therapies would be effective in late disease stages at which human patients would experience symptoms, investigators injected neural progenitor cells into the retinas of laboratory rats at later stages of retinal degeneration.

They also injected neural progenitor cells specifically engineered to express a protein called glial cell line-derived neurotrophic factor (GDNF). They found that cells both without or with the addition of GDNF offered dramatic retinal and vision preservation at both early and later disease stages.

However, GDNF-expressing cells provided better preservation, including broader protection of photoreceptor cells, than did treatment with only neural progenitor cells.

“Neural progenitor cells help preserve the structure of the retina, and the secreted GDNF offers direct photoreceptor protection,” Svendsen said. “Our next step will likely be a study to evaluate the safety of this therapy to eventually pave the way for clinical trials in humans.”

The Journal of Translational Medicine study was supported by California Institute for Regenerative Medicine grants LSP1-08235 and CIRM-EDUC2-08383, and funding from the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

The Stem Cells Translational Medicine study was supported by California Institute for Regenerative Medicine grants LSP1-08235, CIRM-EDUC-08383, CIRM-EDUC2-12638 and CIRM2-12638, and funding from the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

Read More on the Cedars-Sinai Blog: Regenerative Medicine—A New Path for ALS Treatment

“The goal of this group is to create a hub for innovation that propels stem cell science from the laboratory to the bedside,” said Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine, who initiated this new collaboration.

Regenerative medicine uses both gene therapy and stem cell technologies to regenerate tissues within the body to potentially treat a number of diseases, including some that have previously been deemed incurable.

More than 100 people, including the directors of major stem cell institutions, attended a recent three-day summit, funded by a conference grant from the California Institute of Regenerative Medicine (CIRM).

Attendees discussed collaborating on stem cell and gene therapy manufacturing programs, educational courses, core services to support the science, scientific innovations, and new regenerative medicine clinical trials. The following organizations agreed to work collaboratively to accelerate novel regenerative medicine therapies:

• Cedars-Sinai Board of Governors Regenerative Medicine Institute
• University of California, Santa Barbara, Center for Stem Cell Biology and Engineering
• Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the University of Southern California
• University of California, Riverside, Stem Cell Center
• University of California, Irvine, Sue and Bill Gross Stem Cell Research Center
• UCLA Broad Stem Cell Research Center
• City of Hope
• California Institute of Technology

Representatives from these partnering organizations plan to convene annually to discuss collaborative projects and accelerate regenerative medicine projects in California.

“The collaboration is a testament to the importance of regenerative medicine to the field of medicine, as a whole,” said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs, dean of the Medical Faculty, and the Helene A. and Philip E. Hixon Distinguished Chair in Investigative Medicine at Cedars-Sinai. “Initiating this collaboration is also a reflection of the care with which we steward critical funds from grantors like CIRM.”

Read more on the Cedars-Sinai Blog: Treating Diseases with Stem Cells

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Adult cells transformed into an embryonic state—also called induced pluripotent stem cells—are already being used to study ways to repair the body’s tissues and to model human diseases. But this research needs cells, lots of high-quality cells. That’s where biomanufacturing centers like the one at Cedars-Sinai come in.

Dhruv Sareen, PhD, executive director of the Cedars-Sinai Biomanufacturing Center, spoke with the Cedars-Sinai Newsroom about how the center supports medical research, and how a recent $2 million grant from the California Institute for Regenerative Medicine (CIRM) is helping further its mission.

What does the Cedars-Sinai Biomanufacturing Center do?

The Biomanufacturing Center grew out of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and produces cells for both modeling and treating human disease. One major focus is to create induced pluripotent stem cells, or iPSCs, which are cells derived from skin or blood cells that have been reprogrammed back into an embryonic-like state. This allows them to develop into any cell of the body.  

These cells can then be used to create novel models of human disease such as cancer or Parkinson’s disease. Another burgeoning use is reprogramming healthy donor blood cells into iPSCs and creating billions of specialized cells to rejuvenate and provide for therapeutic applications. These cells can be used for treatments, such as to replace dead neurons in patients with Parkinson’s disease or muscular dystrophy, or to create immune cells that act as delivery vehicles to treat cancers.

We also produce gene-modified iPSC lines. These cell lines could be used to target cancer cells more effectively, or to enhance function and transplantation of a regenerative cell therapy.

How do scientists produce stem cell and gene therapies?

We take adult cells, such as from the skin or blood of adults, or cells from umbilical cord blood, and we reprogram them back in developmental time into iPSCs. We do this by temporarily inserting various genes, growth factors and chemicals into the cells. The transformation process takes about a month.

These cells are then isolated and transferred to bigger petri dishes to allow them to multiply and expand. We create large cell “banks” from the cells, called stem cell lines. It takes another two to three months to create a cell line from a few transformed cells.

We can always go back to the cells, whether live or frozen, and create more copies of them in an almost infinite manner.

We also create gene-edited versions of iPS cells using the latest methods, like CRSPR/Cas9, to introduce new genes, delete existing genes, or modify abnormal genes.

Where do the cells go once they’re produced or reprogrammed?

We make some iPS cell lines for investigators within Cedars-Sinai as well as for researchers at other universities and research institutions. We also supply cell lines to investigators at biotech and pharma companies. To date, we have generated over 1,200 iPSC lines.

Our team is also developing iPSCs and gene-edited iPSCs for specific cell therapies for early human clinical trials. We are also working with different types of cells. For example, we are supporting a clinical trial that is studying a potential new cell therapy involving adult retinal stem cells for dry age-related macular degeneration. For this trial, we generate the adult retinal cells in our center under strict U.S. Food and Drug Administration-regulated conditions, put them in a vial and ship them overnight to get transplanted into patients’ eyes the next day.

Every process involved in the life cycle of a production of a cell therapy gets documented and recorded as per U.S. FDA requirements.

How large is the center?

We have about 25,000 square feet of physical laboratory and manufacturing space. We are staffed with 40 scientists, specialists, technicians and assistants, and 10 support staff including managers, administrators, facilities operators, quality assurance staff, and control staff.  

What are some of the center’s biggest accomplishments?

There are many, but to pick a few, in 2017, we were able to obtain approvals to build the facility. Construction was completed in 2020 before the COVID pandemic. We were commissioned and qualified to begin operations in 2021 and then licensed by the California Department of Public Health.  We have created the world’s largest repository of 1,000 iPSCs from patients with amyotrophic lateral sclerosis, also known as ALS, which are available to researchers through our portal. We have also produced the first set of retinal therapy cells that went into patients enrolled in a clinical trial for dry adult macular degeneration. We were also awarded a $3.12 million grant from the Department of Defense to enable creation of clinical-grade iPSC lines and methods to create clinically compatible iPSC-derived vascular endothelial cells to develop future regenerative stem cell treatments for diseases or conditions such as chronic wounds, ischemia, and sepsis.

Most recently we received a $2 million CIRM infrastructure grant to further the mission of the CBC.

How does the CIRM grant help the center meet its goals?

It will improve our operational efficiency, such as our ability to customize and implement electronic quality manufacturing systems for manufacturing cell therapies. The grant will also help us scale up by incorporating machine learning and artificial intelligence into the production of cell lines.

Lastly, the grant will allow us to partner with community colleges to create an internship and training certificate program focused on cell and gene therapies. We’ll train the next generation of regenerative medicine scientists and support staff.

Read more in Discoveries: Stem Cell Science—Separating Myth from Reality

concluded that the reformulated version is less toxic to the heart than the version in wide use since the 1960s.

“Our lab tested this new version of doxorubicin on heart cells that we created from induced pluripotent stem cells—skin or blood cells that have been sent back in time to become stem cells that we can then use to generate any cell type in the human body,” said Arun Sharma, PhD, research scientist in the Board of Governors Regenerative Medicine Institute, the Smidt Heart Institute, Cedars-Sinai Cancer and the Department of Biomedical Sciences at Cedars-Sinai, and co-senior author of the study. “We found that this reformulation is much less toxic to the heart than the original version of the drug, and that could be good news for many cancer patients.”

Early-phase clinical trials of the new formulation have received a green light from the Food and Drug Administration and will soon be underway, Sharma said.

Doxorubicin is a common chemotherapy drug and used to treat breast, bladder and several other cancers, but can cause serious heart damage. To help protect the heart while preserving the drug’s cancer-killing benefits, Xiaojiang Cui, PhD, professor of Surgery at Cedars-Sinai, researcher at Cedars-Sinai Cancer and co-senior author of the study, encapsulated the drug in a protein called albumin.

“Albumin is one of the most common proteins found in the bloodstream, and tumor cells take up a lot of albumin as a nutrient,” Cui said. “We hypothesized that by encapsulating doxorubicin in albumin, more of the drug would be rapidly taken up by tumor cells and less would make its way to the heart.”

Tests of this new version of the drug—called single-protein encapsulated doxorubicin, or SPEDOX-6—showed that human cancer cells robustly took in the encapsulated medication and that it killed the cells efficiently.

Sharma and his team then tested the heart safety of the new formulation.

The team first exposed different cell types within the heart, generated in a dish from stem cells, to traditional doxorubicin and SPEDOX-6, and found that SPEDOX-6 killed fewer of the cells. They also found that human stem cell-derived cardiomyocytes—heart muscle cells that beat even in the laboratory dish—kept beating if exposed to SPEDOX-6 but lost function if exposed to traditional doxorubicin.

SPEDOX-6 also proved less heart toxic when tested on a new laboratory model called 3D cardiac spheroids, previously developed by the Sharma Lab.

“These are 3D spheres made up of fewer than 100,000 heart muscle cells, heart blood vessel cells and other cell types found in the heart,” Sharma said. “They are all grown from stem cells. You can barely see the spheres with the naked eye, but they allow us to rapidly and accurately test the heart toxicity of various substances.”

The team also created stem cell-derived heart cell models from individual cancer patients who had experienced heart damage from doxorubicin treatment—indicating that their hearts were especially vulnerable to the effects of the drug. Again, SPEDOX-6 caused significantly less damage to the cells than the original doxorubicin formulation did.

Going forward, the teams plan to encapsulate other chemotherapy drugs in albumin in the hope of improving both their cancer-killing efficiency and their safety for the heart.

“Widespread use of doxorubicin and other cardiotoxic chemotherapies demonstrates the urgent need to identify effective anti-cancer treatments that are safer for the heart,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai. “These human stem cell-derived models offer a path to identify such treatments and, because of the ability to create patient-specific testing models, also could provide future developments in precision medicine for both cardiology and oncology.”

Other Cedars-Sinai co-authors of this study include first authors Madelyn Arzt and Bowen Gao, as well as Maedeh Mozneb, Stephany Pohlman, Qizhi Liu, Yi Zhang, Xuemo Fan, Amelia Jenkins and Armando Giuliano.

Funding: The study was funded by American Heart Association Career Development Award number 856987; National Institutes of Health grant number 2R01CA151610; Department of Defense grant number W81XWH-18-1-0067; the Uretsky BRCA Research Fund; the Samuel Oschin Comprehensive Cancer Institute Research Development Fund; the Cedars-Sinai Cancer Center; the Fashion Footwear Charitable Foundation of New York, Inc.; the Margie and Robert E. Petersen Foundation; the Linda and Jim Lippman Fund; the Board of Governors Regenerative Medicine Institute at Cedars-Sinai; a NASA In-Space Production Award; the Donna and Jesse Garber Award for Cancer Research; and a California Institute for Regenerative Medicine Bridges Award.

Read more on the Cedars-Sinai Blog: What Are Induced Pluripotent Stem Cells?

The findings, published in the peer-reviewed journal Diabetologia, also identified three therapeutic pathways that reversed these changes and partially restored wound-healing function to the cornea—a discovery that could ultimately inform new treatments for diabetes.

“We have found that diabetes induces more cellular changes than we were aware of previously,” said Alexander Ljubimov, PhD, director of the Eye Program at Cedars-Sinai’s Board of Governors Regenerative Medicine Institute and senior author of the paper. “The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression—what are known as epigenetic alterations.”

More than 37 million people in the United States—11% of the population—have diabetes, a systemic disorder that can result in kidney disease, heart disease, amputation, stroke and nerve damage. Most diabetes drugs are designed to increase glucose tolerance or supply depleted insulin, but do not address molecular and cellular changes or their associated complications.

The new research also identifies for the first time an important role of Wnt-5a, a secreted signaling protein investigators found responsible for corneal wound healing and the function of stem cells—cells capable of differentiating into many cell types.

“Current treatments only address symptoms, so there is an urgent need to understand the molecular mechanisms of diabetes-related wound-healing problems,” said Ruchi Shah, PhD, a scientist in Ljubimov’s lab and the study’s first author. “Understanding of this novel epigenetically regulated wound-healing mechanism could lead to therapeutic treatments that could help patients avoid further long-term ocular health issues.”

Though much focus of diabetic eye disease is on the retina, up to 70% of diabetes patients suffer from problems of the cornea, the transparent, protective exterior surface of the eye. In advanced diabetes, corneal stem cells become dysfunctional, and the cornea heals more slowly and less completely following an injury or procedures such as cataract surgery and laser treatment for diabetic retinopathy.

To identify the epigenetic changes discovered in this study—changes not hard-wired into the genome from birth, but introduced later—Ljubimov and his team compared cells from the corneas from six diabetic patients with those of five healthy donors. They found that in diabetic corneas, the protein product of the WNT5A gene was repressed. Additionally, in diabetic samples, they found an increase in the microRNA that inhibits WNT5A.

The team of scientists then induced wounds to corneal cells in culture and corneal organ cultures, and tested three interventions designed to normalize Wnt-5a protein expression. They added the Wnt-5a protein directly; they introduced a DNA methylation inhibitor, originally approved to treat cancer; and they targeted microRNA levels with a novel gene therapy approach using a nanoscale compound. The team developed the compound, which uses synthetic molecules to block the microRNA, as a substitute for a viral gene therapy they found to be toxic to stem cells.

All three therapeutic methods, in the diabetic samples, stimulated stem cell marker production and improved tissue regeneration, accelerating wound healing.

“Novel therapies to reverse epigenetic effects could improve corneal function, and may also prove significant in other diabetic complications,” said Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute and study co-author. “This work certainly helps move the field forward.”

Investigators will continue to analyze their data to better understand the mechanisms of WNT5A and other genes related to wound healing. They are also studying a combination therapy to target both microRNA and DNA methylation in hopes that it will more thoroughly normalize wound healing by increasing Wnt-5a protein.

“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” said Ljubimov. “Drugs that are FDA [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies.”

Funding: This work was funded by National Institutes of Health grant numbers R01EY013431482, R01EY031377, R01EY025377, and R01CA206220; and the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

Read more on the Cedars-Sinai Blog: Diabetes Dealt Her In and She’s Playing to Win