Hematopoietic stem and progenitor cell hierarchy is established by thrombopoietin-driven neonatal hematopoiesis

The cytokine thrombopoietin (THPO) promotes both self-renewal and cell cycle quiescence of adult bone marrow (BM) hematopoietic stem cells (HSCs). It remains unclear how THPO differentially regulates HSC expansion versus quiescence and whether it influences the broader BM hematopoietic hierarchy, particularly multipotent progenitor cells (MPPs), which express MPL, the receptor for THPO. Adult constitutional Thpo-knockout mice exhibited significant decrease in both HSC and MPP numbers, yet single-cell RNA sequence-based genetic changes were prominent only in HSCs. Induced deletion of Thpo in adult mice showed that THPO primarily maintains adult BM HSC numbers by inhibiting apoptosis. Thpo deficiency-driven reduction of adult BM MPPs was attributed to the shortage of expansion and differentiation of HSCs during neonatal BM hematopoiesis. Drug-mediated enhancement of THPO signaling in neonatal Thpo-deficient mice rescued adult BM progenitor cell numbers but not HSC apoptosis. THPO function is thus limited during adult hematopoiesis but is critical during neonatal development to establish a structured HSC and MPP hierarchy.