Solving a 50-Year Mystery on Stem Cell Transplants

A study published in Nature by researchers at the Wellcome Sanger Institute and the University of Zurich has revealed how donor age affects the long-term success of stem cell transplants, finally solving a 50-year mystery regarding cellular behavior post-transplant.

By tracking the behavior of transplanted stem cells up to three decades post-transplant, this research offers new insights that could improve donor selection and patient outcomes.

Understanding stem cell transplants

Stem cell transplants, often called bone marrow transplants, are life-saving procedures used to treat severe blood-related conditions, including certain cancers like leukemia and lymphoma. These disorders can disrupt the normal function of a person’s blood and immune system, often rendering it ineffective or harmful to the body. Over a million people worldwide are diagnosed with blood cancer each year, and for these patients, a stem cell transplant may be the only curative option. In 2021, over 22,000 hematopoietic cell transplants were performed in the United States.

For this procedure, the patient first undergoes chemotherapy or radiation to destroy the faulty cells within their bone marrow. Healthy hematopoietic stem cells from a donor are then infused into the patient’s bloodstream. These stem cells, if successful, travel to the bone marrow and begin the complex process of regenerating the entire blood and immune system, producing the red blood cells, white blood cells and platelets necessary for proper immune function and circulation.

While stem cell transplants have been used for over half a century, their outcomes vary widely. Factors such as donor compatibility, age and genetic differences can affect transplant success, making this a complex and high-stakes procedure with the potential for complications. Historically, the medical community’s understanding of the long-term behavior of these transplanted cells in patients has been limited. Now, lead author Dr. Michael Spencer Chapman, director of health informatics at the Wellcome Sanger Institute, and his team are revealing fresh insights into how transplants work at a cellular level.

“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,” said Chapman.

How donor age impacts transplant success

The team analyzed genomic sequences from over 2,800 blood samples taken from 10 donor-recipient sibling pairs from up to 9–31 years post-transplant.

In transplants from younger donors (ages 18–47), up to 30,000 stem cells were successfully engrafted and continued contributing to blood production long-term. In contrast, transplants from older donors (ages 50–66) showed a tenfold decrease, with only between 1,000-3,000 stem cells surviving and maintaining function over time.

The engrafted stem cells retained the ability to produce diverse blood cell types, including myeloid cells and B and T lymphocyte; however, the team found individual clones often favored one type of mature blood cell over others, which may influence the immune system’s adaptability post-transplant. Additionally, transplanted stem cells showed 10–15 years’ worth of accelerated aging in clonal diversity compared to the donor’s cells, primarily due to a decline in stem cell diversity.

By mapping somatic mutations and epigenetic changes in transplanted cells that endure selection pressures, the study suggests that identifying key genetic pathways could help enhance the diversity and resilience of engrafted cells. This insight could guide future improvements in donor selection and pre-transplant conditioning strategies.

Identifying genes to improve stem cell transplants

“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,” said Chapman.

“The research highlights that age is more than just a number – it’s an important factor in transplant success. 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,” said senior author Dr. Markus Manz, the director of the department of medical oncology at the University of Zurich.

The team hopes their research will enable them to identify which genes carry somatic mutations or epigenetic changes enriched at different stages of the transplant procedure.

“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,” said corresponding author Dr. Peter Campbell, a senior group leader and the head of cancer, aging and somatic mutation at the Wellcome Sanger Institute.

The findings demonstrate that the age of the donor massively impacts transplant outcomes. This aligns with the decision made by the notable hematopoietic stem cell transplantation charity Anthony Nolan, to lower the recruitment age of their stem cell register to 16, aiming to provide more patients in need of an unrelated donor with the best possible transplant results.

Reference: Spencer Chapman M, Wilk CM, Boettcher S, et al. Clonal dynamics after allogeneic haematopoietic cell transplantation. Nature. Published online October 30, 2024. doi:10.1038/s41586-024-08128-y

This article is a rework of a press release issued by the Wellcome Sanger Institute. Material has been edited for length and content.