New research on the long-term dynamics of transplanted stem cells in a patient's body reveals how age affects stem cell survival and immune diversity, providing insights that could make transplants safer and more successful.
For the first time, scientists have discovered what happens to stem cells decades after transplant, lifting the curtain on a process that has been a medical mystery for more than 50 years. The insights could lead to new strategies in donor selection and transplant success, potentially leading to safer, more effective transplants.
Researchers at the Wellcome Sanger Institute and their colleagues at the University of Zurich were able to map the behavior of stem cells in recipients' bodies up to three decades after transplant, providing the first glimpse of the long-term dynamics of these cells. ,
The study, published October 30 NatureTurns out that transplants from older donors, which are often less successful, have ten times fewer vital stem cells surviving the transplant process. Some living cells also lose the ability to produce a range of blood cells needed for a strong immune system.
More than one million people worldwide are diagnosed with blood cancers each year, including cancers such as leukemia and lymphoma, which can prevent a person's immune system from functioning properly. Stem cell transplantation, also known as bone marrow transplantation, is often the only curative treatment option for patients.
This procedure replaces the patient's damaged blood cells with healthy stem cells obtained from a donor, which then rebuild the patient's entire blood and immune system. In the UK alone, more than 2,000 people undergo the procedure each year.
Despite being performed for more than 50 years, many basic questions about how transplantation works remain unanswered. Although they can be lifesaving, outcomes vary widely, with many patients experiencing complications years later. It is known that the age of the donor affects success rates, but what happens at the cellular level after transplantation has been a “black box” until now.
In this new study, researchers from the Wellcome Sanger Institute and the University of Zurich used advanced genome sequencing techniques to analyze blood samples from ten donor-recipient brother-sister pairs up to 31 years after transplant.
By analyzing the life-long mutations that occur in the donor and recipient's stem cells, they can track how many stem cells survived the transplant process and continued to produce new blood cells in the patient's body – an approach previously impossible.
The team found that in transplants from younger donors – those in their 20s and 30s – about 30,000 stem cells survived longer, while only 1-3,000 stem cells survived from older donors. This decline may lead to reduced immunity and a higher risk of recurrence, which potentially explains why younger donors often result in better outcomes.
They also found that the transplant procedure prolongs blood function in recipients by about 10–15 years compared to matched donors, primarily due to less stem cell diversity.
Surprisingly, despite the intense stress of the transplant process, the stem cells contain few new genetic mutations as they rapidly divide to reconstitute the patient's blood. This challenges previous assumptions about high mutation rates during transplantation.
The study also identified other genetic factors that help certain stem cells thrive after transplant, regardless of the age of the donor. This range of genetic advantages could lead to the development of better treatments, making transplants safer and more effective for a wider range of patients.
Dr. Michael Spencer Chapman, first author of the study at the Wellcome Sanger Institute, said, “When you get a transplant, it's like giving your blood system a fresh start, but what actually happens to those stem cells? Until now, all we could do was introduce the cells and then monitor blood counts for signs of recovery.
“But in this study we detected decades of changes in the same sample, revealing how some cell populations die out while others dominate, shaping the patient's blood over time. It's exciting to understand this process in such detail.”
Dr. Markus Manz, senior author of the study at the University of Zurich, said, “The research highlights that age is more than just a number – it is an important factor in transplant success. However, the hematopoietic stem cell system changes surprisingly well over time. Although morphologically stable, younger donors generally supply a larger and more diverse range of stem cells, which may be important for the long-term recovery of patients.
“We hope to continue to discover other factors that influence long-term hematopoietic stem cell dynamics in order to fine-tune both donor selection as well as the recipient bone-marrow environment for optimal long-term stem cell function.”
“The transplant process forces the blood and immune cells to undergo a kind of genetic 'bottleneck,'” said Dr. Peter Campbell, senior author of the study at the Wellcome Sanger Institute. Our new approach allows us to examine this barrier phenomenon more closely.
“We have found that the barrier provides many different opportunities for some stem cells to thrive more than others in their new environment in the recipient. We believe that some stem cells will thrive better than others.” It would be possible to find the genes responsible for enabling a transplant to thrive – these genes could then theoretically be used to improve the success of the transplant process.”
More information:
Peter Campbell, Clonal dynamics after allogeneic hematopoietic cell transplantation using genome-wide somatic mutations, Nature (2024). doi:10.1038/s41586-024-08128-y. www.nature.com/articles/s41586-024-08128-y
Provided by the Wellcome Trust Sanger Institute
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