Adult hematopoietic stem cells (HSCs) sustain the lifelong production of all mature blood and immune cells. HSCs possess extensive regenerative potential, but their self-renewal is limited. A long-standing question has been why replicative history negatively impacts HSC functions. We found that accrued divisions alter HSC production; generating low-output bone-marrow landscapes that are highly variable in lineage contribution and transcriptionally divergent within individual lineages. Division-driven HSC functional alterations arise from redirecting branched chain amino acid (BCAA) usage from catabolic towards anabolic activity, causing faster HSC cell cycle kinetics. Adding a BCAA transamination product overcomes the BCAA catabolic checkpoint and slows down the cell cycle, durably rescuing balanced lineage output of HSCs with accrued divisions. Hence, our study suggests the paradigm whereby replicative history causes metabolic and transcriptional drift, generating divergent HSC output. Division-dependent HSC functional drift can be restored by metabolite replacement, which has long-term therapeutic implications for HSC regenerative medicine.
