Metabolic checkpoint controls hematopoietic stem cell replicative lifespan (Bulk RNA-Seq)

Adult hematopoietic stem cells (HSCs) sustain the lifelong production of all mature blood and immune cells. HSCs possess extensive regenerative potential, but the actual self-renewal of HSCs is limited. A long-standing question has been why replicative history negatively impacts HSC lineage-generating capacity. We found that accrued divisions durably alter HSC production; generating low-output bone-marrow landscapes that are highly variable in both lineage contribution and transcriptional divergence within individual lineages. Mechanistically, division-driven functional alterations in HSCs are due to redirecting branched chain amino acid (BCAA) usage from catabolic towards anabolic activity, causing faster HSC cell-cycle kinetics. Adding a BCAA deaminated product is sufficient to bypass the BCAA catabolic checkpoint and slow down the cell cycle, durably rescuing balanced lineage output of HSCs with accrued divisions. Hence, our study suggests a novel 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.