'Black box' of stem cell transplants opened in blood study

Insights could pave the way for new strategies in donor selection and transplant success, potentially leading to safer, more effective transplants.

Researchers from the Wellcome Sanger Institute and their collaborators at the University of Zurich were able to map the behaviour of stem cells in recipients' bodies up to three decades post-transplant, providing the first-ever glimpse into the long-term dynamics of these cells.

The study, published today (30 October) in Nature and part-funded by Cancer Research UK, reveals that transplants from older donors, which are often less successful, have ten times fewer vital stem cells surviving the transplant process. Some of the surviving cells also lose the ability to produce the range of blood cells essential for a robust immune system.

Over a million people worldwide are diagnosed with blood cancer each year¹, including cancers such as leukaemia and lymphoma, which can stop a person's immune system working properly. Stem cell transplants, also known as bone marrow transplants, are often the only curative treatment option for patients. The procedure replaces a patient's damaged blood cells with healthy stem cells from a donor, which then rebuild the patient's entire blood and immune system. In the UK alone, over 2,000 people undergo this procedure each year².

Despite being performed for over 50 years, many fundamental questions about how transplants work have remained unanswered. While they can be life-saving, outcomes vary widely, leaving many patients facing complications years later. Donor age has been known to impact success rates³, but what happens at the cellular level following a transplant 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 analyse blood samples from ten donor-recipient sibling pairs up to 31 years post-transplant⁴.

By analysing the mutations that occur throughout life in the donor and recipient's stem cells, they could track how many stem cells had survived the transplant process and continued to produce new blood cells in the patient's body -- an approach previously impossible.

The team discovered that in transplants from younger donors -- those in their 20s and 30s -- about 30,000 stem cells survive long-term, compared to only 1-3,000 in older donors. This drop could lead to reduced immunity and higher relapse risk, potentially explaining why younger donors often result in better outcomes.

They also found that the transplant process ages the blood system in recipients by about10-15 years compared to the matched donors, primarily due to lower stem cell diversity.

Surprisingly, despite the intense stress of the transplant process, stem cells gain few new genetic mutations as they rapidly divide to rebuild the patient's blood. This challenges previous assumptions about high mutation rates during transplantation.

The study also identified other genetic factors regardless of the donor's age that help certain stem cells thrive following transplant⁵. 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 receive a transplant, it's like giving your blood system a fresh start, but what actually happens to those stem cells? Until now, we could only introduce the cells and then just monitor the blood counts for signs of recovery. But in this study we've traced decades of changes in one single sample, revealing how some cell populations fall away while others dominate, shaping a patient's blood over time. It is 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's an important factor in transplant success. Although the hematopoietic stem cell system is amazingly stable over time, younger donors generally supply a larger and more diverse range of stem cells, which might be crucial for patients' long-term recovery. We hope to continue exploring other factors that affect long-term hematopoietic stem cell dynamics in order to fine-tune both donor selection as well as recipient bone-marrow environments for optimal long-term stem cell function."

Dr Peter Campbell, senior author of the study at the Wellcome Sanger Institute, said: "The transplant process forces blood and immune cells through a type of genetic 'bottleneck'. Our new approach allows us to investigate this bottleneck phenomenon more closely. We find that the bottleneck provides multiple different opportunities for some stem cells to thrive more than others in their new environment in the recipient. We believe it will be possible to find the genes responsible for enabling some stem cells to thrive better than others -- these genes could then in theory be harnessed to improve the success of the transplant procedure."

1. https://www.worldwidecancerresearch.org/information-and-impact/cancer-myths-and-questions/what-is-blood-cancer-and-why-do-we-need-more-research/#:~:text=Blood%20cancers%20are%20the%20fifth,were%20diagnosed%20worldwide%20in%202020
2. https://www.blood.co.uk/news-and-campaigns/news-and-statements/nhsbt-celebrates-stem-cell-donors-and-transplants/
3. https://www.anthonynolan.org/blog/2018/02/23/research-shows-donor-age-most-important-in-stem-cell-transplant-survival
4. In the study, the donor is considered the 'control'. By comparing the genetic changes in both donor and recipient blood samples through whole genome sequencing, the team reconstructed their evolutionary history to understand how the cells have adapted and changed since the transplant. These samples were taken between 9 to 31 years post-transplant.
5. Some stem cells had advantages before the transplant, allowing them to better adapt to their new environment in the recipient's body. These included better survival during harvesting or preparation, while others gained an edge after transplant due to genetic mutations that allowed them to thrive in the recipient's bone marrow. Understanding these patterns could help doctors improve the transplant process and better select which stem cells are likely to succeed, regardless of the donor's age.