CD38 inhibition preserves adult human hematopoietic stem cells

Abstract In humans, long-term hematopoietic stem cells (LT-HSCs) are enriched within the CD34⁺CD38 low fraction in vivo, and CD38 abundance typically rises with lineage commitment, suggesting that CD38 may function as a negative regulator of stem cell function. Here, we show that pharmacologic CD38 inhibition with 78c during 7-day culture preserves adult human LT-HSC repopulating activity, yielding durable primary and secondary engraftment and limiting-dilution-estimated LT-HSC frequencies comparable to uncultured controls. Transcriptomic and proteomic profiling revealed coordinated repression of PI3K–AKT–mTOR–linked anabolic and G₁–S programs, with increased signatures of quiescence, chromatin compaction, and stress resilience. Pharmacologic inhibition of mTOR, PI3K, or CDK activity phenocopied the effects of 78c on cell cycle restraint and HSC maintenance. These findings support a model in which CD38 inhibition restrains mTOR-gated entry into cycle in cytokine-stimulated cultures, and identify CD38 inhibition as a tractable strategy to preserve adult human LT-HSCs ex vivo.