New studies focusing on the enduring behavior of transplanted stem cells provide new insights into how age influences their survival and immune diversity, potentially enhancing the safety and success rates of transplants.
For the first time, researchers have monitored the fate of stem cells even decades after a transplant, shedding light on a procedure that has been enigmatic for over half a century.
These findings could lead to innovative methods for selecting donors and improving transplant outcomes, making procedures safer and more effective.
A team from the Wellcome Sanger Institute, in collaboration with the University of Zurich, successfully mapped the behavior of stem cells in recipients up to 30 years after their transplants, providing unprecedented insights into their long-term dynamics.
Published on October 30 in Nature, and supported in part by Cancer Research UK, the research shows that transplants from older donors, which often yield poorer results, have tenfold fewer surviving crucial stem cells post-transplant. Additionally, many surviving cells may lose their ability to produce a full range of blood cells critical for a healthy immune system.
Each year, over one million individuals globally are diagnosed with blood cancers, including leukaemia and lymphoma, which can disrupt the function of the immune system. Stem cell transplants, also referred to as bone marrow transplants, are frequently the only curative treatment available, replacing the patient’s damaged blood cells with healthy stem cells from a donor to regenerate the entire blood and immune system. In the UK, more than 2,000 individuals undergo this procedure annually.
Despite its long history, many essential questions surrounding the mechanics of transplants have remained unresolved. While they can be lifesaving, the results vary significantly, with many patients encountering complications years later. The age of the donor is known to affect success rates, but the cellular processes occurring after a transplant have been largely unknown until now.
In this study, researchers utilized advanced genome sequencing methods to examine blood samples from ten pairs of donor-recipient siblings for up to 31 years after the transplant.
By analyzing the mutations that accrue over a lifetime in the donor’s and recipient’s stem cells, they were able to determine how many stem cells survived the transplant and continued to generate new blood cells within the patient’s body—a previously unattainable method.
The findings revealed that around 30,000 stem cells from younger donors in their 20s and 30s survive long-term, compared to merely 1,000 to 3,000 from older donors. This significant decline may contribute to diminished immunity and increased relapse risks, which could explain the improved outcomes associated with younger donors.
The research also indicated that the transplant procedure ages the recipient’s blood system by roughly 10 to 15 years compared to their matched donor, largely due to reduced stem cell diversity.
Contrary to previous beliefs that high mutation rates occur during the transplant process, it was surprising to find that stem cells gain few new genetic mutations as they quickly divide to restore the patient’s blood.
Moreover, the study identified other genetic factors that aid certain stem cells in thriving after transplantation, irrespective of the donor’s age. These genetic advantages could facilitate the development of enhanced treatments, thereby improving the safety and efficacy of transplants for a broader range of patients.
Dr. Michael Spencer Chapman, the lead author from the Wellcome Sanger Institute, stated, “Getting a transplant resembles giving your blood system a fresh start, but what genuinely transpires with those stem cells? Previously, we could only introduce the cells and watch blood counts for signs of recovery. In this research, we’ve traced decades of evolution from a singular sample, discovering how some cell groups diminish while others prevail, influencing a patient’s blood composition over time. It’s thrilling to unravel this process in such depth.”
Dr. Markus Manz, the senior author from the University of Zurich, added, “The findings underscore that age is more than merely a number—it plays a critical role in transplant success. Although the blood stem cell system remains remarkably stable over time, younger donors typically provide a broader and more diverse stem cell range, which may be vital for patients’ long-term recovery. We intend to continue researching other factors influencing prolonged hematopoietic stem cell behavior to refine donor selection and enhance recipient bone marrow environments for optimal stem cell function in the long run.”
Dr. Peter Campbell, another senior author from the Wellcome Sanger Institute, remarked, “The transplant process forces blood and immune cells through a kind of genetic ‘bottleneck’. Our innovative method enables us to examine this bottleneck phenomenon more intricately. We’ve discovered that this bottleneck presents various opportunities for certain stem cells to flourish more than others within the recipient’s new environment. We believe it is feasible to identify the genes responsible for enabling some stem cells to thrive more efficiently than others—these genes could potentially be used to advance transplant success.”
- 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
- https://www.blood.co.uk/news-and-campaigns/news-and-statements/nhsbt-celebrates-stem-cell-donors-and-transplants/
- https://www.anthonynolan.org/blog/2018/02/23/research-shows-donor-age-most-important-in-stem-cell-transplant-survival
- In this research, the donor serves as the ‘control’. By comparing the genetic changes in the blood samples from both donor and recipient using whole genome sequencing, the team reconstructed their evolutionary history to comprehend how the cells have adapted and transformed since the transplant. These samples were collected between 9 and 31 years post-transplant.
- Some stem cells possessed pre-existing advantages before the transplant, enabling them to better adapt to the new environment in the recipient’s body. These advantages included superior survival during the harvesting or preparation stages, while other benefits arose post-transplant due to genetic mutations that allowed certain cells to succeed in the recipient’s bone marrow. Understanding these trends could assist doctors in enhancing transplant procedures and in selecting which stem cells are more likely to thrive, regardless of the donor’s age.
