A Distinct Subset of Human Blood Stem Cells Resists Regenerative Stress to Preserve Stemness

Abstract

Life-long hematopoiesis is ensured by delicately balancing the hematopoietic stem cell (HSC) pool between long-term maintenance and meeting the demands of both normal blood production (~1011 cells/day) and unexpected stress conditions. Using xenotransplantation assays and cell purification, we show that there are distinct subsets of human long-term (LT-)HSC that respond differently to regeneration-mediated stress: a CD112low subset that exhibits a transient restraint (termed latency) before contributing to hematopoietic reconstitution and a primed CD112high subset that responds rapidly. These distinct stemness states are governed by an INKA1/PAK4/H4K16ac axis where CD112low LT-HSC exhibit high INKA1 and low H4K16ac, marking an alternative state of quiescence that serves to preserve self-renewal and regenerative capacity upon successive rounds of regeneration-mediated stress. Collectively, our data uncover a new molecular axis for HSC self-renewal regulation and point to latency as an orchestrated physiological response that integrates quiescence control with HSC fate choices to maintain LT-HSC pool size.