Understanding the Dynamics of Stem Cells

Age significantly influences stem cell survival and immune diversity, according to new research on the long-term behavior of transplanted stem cells in patients. These findings could help improve the safety and efficacy of stem cell transplants.

Researchers have, for the first time, tracked stem cells for decades post-transplant, revealing key insights into this previously mysterious process. This knowledge opens doors to new approaches in donor selection and transplant success, with potential to make transplants safer and more effective.

In collaboration, researchers from the Wellcome Sanger Institute and the University of Zurich mapped stem cell behavior in recipients up to 30 years post-transplant, offering the first-ever view of long-term dynamics. Published in Nature with support from Cancer Research UK, the study shows that transplants from older donors—often less successful—have up to ten times fewer viable stem cells. Additionally, some remaining cells lose the ability to produce the diverse blood cells required for a healthy immune system.

Each year, more than a million people globally are diagnosed with blood cancers like lymphoma and leukemia, which can weaken immune function. For many, stem cell (or bone marrow) transplants are the only viable treatment. This procedure replaces damaged blood cells with healthy stem cells from a donor, rebuilding the patient’s blood and immune systems. In the UK alone, over 2,000 people undergo this operation annually.

While transplants have been performed for over 50 years, fundamental questions remain. Success rates vary, and many patients face complications years later. Although younger donors are associated with better outcomes, the cellular mechanisms post-transplant have been largely unknown—until now.

Using genome sequencing, researchers examined blood samples from ten sibling donor-recipient pairs up to 31 years after transplantation. By analyzing mutations that accumulate in stem cells over time, they could identify the number of stem cells that survived the transplant and continued generating new blood cells—something previously unattainable.

Findings revealed that transplants from younger donors (in their 20s and 30s) resulted in approximately 30,000 surviving stem cells, while transplants from older donors yielded only 1,000–3,000. This reduced stem cell count correlates with lower immune resilience, potentially explaining why transplants from younger donors are more successful.

Moreover, the transplant process was found to age recipients’ blood systems by 10–15 years compared to matched donors, primarily due to reduced stem cell diversity.

Interestingly, despite the stress of the transplant process, stem cells accumulate relatively few new mutations during the rapid cell division needed to rebuild the patient’s blood. This challenges previous assumptions about high mutation rates in transplants.

The study also identified genetic factors, beyond donor age, that help certain stem cells thrive after a transplant. Understanding these factors could lead to new treatments, making transplants safer and more effective for a broader range of patients.

Dr. Michael Spencer Chapman, first author and Health Informatics Director at the Wellcome Sanger Institute, explains: “A transplant gives the blood system a fresh start, but we’ve only been able to monitor it through blood counts. This study allows us to trace changes over decades, showing how some cell populations fade while others dominate. It’s exciting to understand this process in such detail.”

Dr. Markus Manz, senior author from the University of Zurich, adds: “Age is a crucial factor in transplant success. While the hematopoietic stem cell system is remarkably stable over time, younger donors generally supply a more diverse range of stem cells, which could be key for long-term recovery. We aim to continue studying factors that optimize both donor selection and recipient environments for the best long-term outcomes.”

Dr. Peter Campbell, senior author from the Wellcome Sanger Institute, noted: “Transplants create a genetic bottleneck for blood and immune cells. Our approach lets us closely examine this bottleneck, finding that it offers unique opportunities for some stem cells to thrive. Identifying genes that allow certain stem cells to thrive could improve transplant success rates.”

Dr. Tania Dexter, Medical Officer at Anthony Nolan, a UK charity connecting stem cell donors with patients in need, commented: “This study provides remarkable insight into what happens to cells decades after a stem cell transplant. The findings support our own research showing that donor age matters, reinforcing our decision to lower the donor registration age to 16. Studies like this are essential for improving transplant outcomes and helping more patients survive and thrive.”