Transplantation Dose Alters the Differentiation Program of Hematopoietic Stem Cells

• 70%–80% HSC clones do not supply every blood cell type in the presence of other HSCs
• HSC differentiation changes with the transplantation dose
• Maximum blood production by a single HSC is unaffected by transplantation dose
• High transplantation doses increase the number of short-term differentiating clones

SummaryHematopoietic stem cell (HSC) transplantation is the most prevalent stem cell therapy, but it remains a risky procedure. To improve this treatment, it is important to understand how transplanted stem cells rebuild the blood and immune systems and how this process is impacted by transplantation variables such as the HSC dose. Here, we find that, in the long term following transplantation, 70%–80% of donor-HSC-derived clones do not produce all measured blood cell types. High HSC doses lead to more clones that exhibit balanced lymphocyte production, whereas low doses produce more T-cell-specialized clones. High HSC doses also produce significantly higher proportions of early-differentiating clones compared to low doses. These complex differentiation behaviors uncover the clonal-level regeneration dynamics of hematopoietic regeneration and suggest that transplantation dose can be exploited to improve stem cell therapy.

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