The protein restores the blood stem cell niche—the specialized environment that supports blood-forming stem cells—allowing the bone marrow to resume producing the blood cells the body needs.

Their preclinical study, published in Blood, could yield future treatments that help cancer patients recover faster after chemotherapy and radiation.

“The mechanisms that govern how the blood stem cell niche recovers after injury are not well understood,” said John Chute, MD, director of the Division of Hematology and Cellular Therapy at Cedars-Sinai and senior author of the study. “We identified a mechanism that stimulates niche recovery, which opens an exciting avenue to help patients replenish their entire blood system after chemotherapy or radiation.”

Chute compared the niche to the soil in a garden in which blood stem cells—which generate all of the body’s blood cells—blossom or grow. The niche is made up of several types of cells that tend to the blood stem cells, spurring them to divide and multiply so that they can replace blood cells that are damaged or lost.

“Chemotherapy and radiation therapy cause severe DNA damage to the niche cells,” Chute said. “The blood stem cells can’t regenerate because of this damage to their ‘soil,’ and this depletes the patient’s blood count for weeks.”

For patients, this means debilitating fatigue and increased risk of infection, bleeding and prolonged hospitalization.

Investigators found that a protein called R-spondin 2, which amplifies the signaling in cells that line blood vessels in the bone marrow, speeds up the recovery of the niche. 

When investigators treated laboratory mice that had been exposed to total body irradiation with R-spondin 2, the blood stem cell niche—specifically the cells lining the blood vessels in the niche—recovered more quickly than in untreated mice.

A key and surprising finding was that R-spondin 2 acted on the vascular niche cells, rather than the blood stem cells themselves.

Chute said that these findings may open the door to future research focused on the discovery and augmentation of mechanisms for niche repair. Targeting such mechanisms could accelerate the recovery of patients receiving chemotherapy or undergoing stem cell transplantation.

“Our outcomes for patients undergoing blood and marrow transplant are exceptional,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “This type of translational research can yield further improvements for those patients and all patients undergoing chemotherapy or radiotherapy.”

Additional Cedars-Sinai authors include Vanessa N. Montinelli, Samantha Grohe, Xue Ying Song, Jacqueline Turnlund, Hannah Hackbart, Joshua Sasine, Morgan Brady, Masahiro Muraoka, Rucha Kadam, Flavia D. Cavicchioli, Sage Kang, Ashley Dawson, Mimoli Uehara, Courtny Dizon, Theresa Krack, Peibin Yue, and Yuwei He.

The paper’s other author is Kurt D. Hankenson, University of Michigan.

Funding: This work was funded, in part, by NIAID awards U01 AI159622 (PI: John Chute), R21 AI193964 and NHLBI award R01 HL086998 (PI: John Chute).

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.

These outcomes place the medical center at the top of rankings recently released by the Center for International Bone and Marrow Transplant Research (CIBMTR). Cedars-Sinai is one of just seven adult transplant centers out of 176 in the U.S. where patient survival after transplant is significantly better than predicted.

“We have a carefully chosen approach to pretransplant conditioning and graft-versus-host disease prevention for our patients, which plays a vital role in our strong survival outcomes,” said John Chute, MD, director of the Division of Hematology and Cellular Therapy at Cedars-Sinai Cancer. “We also have a dedicated system for keeping patients in touch with their care team, which helps identify problems before they become serious.”  

The greatest risk to stem cell transplant patients is during the first 100 days after transplant, said Ronald Paquette, MD, clinical director of the Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai Cancer.  

“We have modified our pretransplant regimens and post-transplant care to minimize toxicity to the patients and give them the best chance for a successful recovery,” Paquette said. “We also are careful to select stem cell donors who can provide the best-quality stem cell and immune cell recovery.”

An allogeneic transplant uses stem cells from a donor, rather than the patient’s own cells, and Paquette said the approaches to these transplants are specific to each institution.

Along with a uniform approach to pretransplant therapy, Chute and Paquette attributed Cedars-Sinai’s top ranking to the frequent use of younger half-matched donors—often a child or grandchild of the patient—to get patients to transplant more quickly.

“In addition to that, there is no replacement for the people who take care of the patients, from the transplant coordinators to the physicians, nurses and advanced practice providers,” Chute said. “The dedication of our team provides that crucial element that yields the best possible results for our patients.”

Chute and Paquette are currently exploring stem cell transplant for patients who would once have been thought “too old” for the procedure.

“Age 75 used to be the upper limit, but that was arbitrary,” Paquette said. “We have transplanted several patients over age 75 and all are doing well so far. We are hoping to learn more about the biology of transplant via these patients, to learn about the pluses and minuses of doing transplants in patients this age. We want to learn not only how to extend their survival but also how to maximize their quality of life.”

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 Blood and Marrow Transplant Program in the Division of Hematology and Cellular Therapy at Cedars-Sinai Cancer was one of just 12 among 172 adult transplant programs where patient survival one year after transplant exceeded expectations, according to 2024 rankings from the Center for International Blood and Marrow Transplant Research. Survival rate at Cedars-Sinai was 90%, which far exceeded the expected survival outcome of 68%-83%.

“We’ve made a variety of changes during the past several years that have had a dramatic impact on our patient outcomes,” said Ronald Paquette, MD, clinical director of the Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai.

One important change, Paquette said, was routine use of the chemotherapy drug cyclophosphamide after each transplant. This helps prevent graft-versus-host disease, which causes the patient’s immune system to attack the recipient’s organs.

“That one change, which has since been validated through published research, led to an almost immediate 20% improvement in one-year survival rates,” Paquette said. “What we have done since then has been to fine-tune our processes.”

These refinements have included an adjustment to the therapies used to prepare a patient for transplantation, which is called a conditioning regimen. The therapies in the conditioning regimen kill the cancer cells in the patient’s body, make room in the patient’s bone marrow for the transplanted stem cells to grow, and help prevent the patient’s immune system from attacking the new cells.

“There are many possible combinations, and we initially tried to match the conditioning therapy to each patient’s specific disease scenario,” Paquette said. “What we have learned by carefully tracking patient outcomes is that it is more important to choose a regimen that pairs well with the posttransplant cyclophosphamide. Some combinations caused excessive toxicities to the kidneys and the lungs. We have narrowed our conditioning regimens to two that we have found to work best.”

Another improvement has come from a gradual increase in the number of transplants using half-matched donors—often a child or an extended family member—rather than a donor with a perfectly matched tissue type.

“For these half-matched transplants, the donors are most often children, nieces, nephews or even grandchildren,” Paquette said. “The median age for our transplant patients is 68 to 70, and our half-matched donors might be 30 or 40 years younger than the recipient. We’ve found that younger donors yield substantially better outcomes than older donors, and now 85% of our transplants are performed using these half-matched donors.”

John Chute, MD, director of the Division of Hematology and Cellular Therapy at Cedars-Sinai Cancer, attributes these improvements and the resulting run of high rankings to Paquette and the stem cell transplantation team.

“This ranking is a great tribute to Dr. Paquette, and to our amazing physicians, administrative staff, nurse practitioners, nurses, and other members of the care team,” Chute said. “There are many working parts to the transplant process and our stellar outcomes wouldn’t be possible without the expertise of a number of different people who provide the attentive care our patients need.”

The transplant team continues to investigate avenues for further refining their process, Paquette said. They are working to develop options for offering transplants to a broader range of patients, and to better understand the interaction between stem cells and host bone marrow and the effects of intestinal bacteria on the transplant process.

“Our current process is producing great outcomes, and through strategic steps we are continuing to refine it,” Paquette said. “Through all of these efforts, we hope to learn things that will help us further improve therapies in the future.”

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.