Programming of the fetal hematopoietic stem and progenitor cell compartment

Developmental origins of disease in the hematopoietic system remain poorly understood despite rising pediatric hematologic and immune disorders. Fanconi anemia (FA), the most common inherited bone marrow failure syndrome, is traditionally attributed to postnatal stem cell loss. Using Fancc-deficient mouse models, we demonstrate a prenatal deficit in fetal liver hematopoietic stem and progenitor cells (HSPCs), including reduced repopulating capacity and cell cycle arrest. Increased γH2AX foci and upregulation of DNA repair genes indicate heightened susceptibility to DNA damage absent external stressors. These findings suggest congenital defects in hematopoiesis contribute to FA pathogenesis, highlighting the fetal hematopoietic compartment as a critical target.