Sex differences in hematopoietic progenitors: defining the roles of gonadal vs chromosomal sex 2259359

Abstract Introduction Hematopoietic stem and progenitor cells (HSPC) self-renew and differentiate throughout the lifespan to maintain blood cell populations in homeostasis and regenerate after injury. HSPCs (e.g. long-term (LT) and short-term (ST) HSCs and multipotent progenitors (MPPs) express androgen and estrogen receptors. Sex differences in HSPC numbers and fitness may arise from epigenetically imprinted events originating from an original sex steroid exposure or be reshaped by the extrinsic sex steroid environment. Sex differences in HSPCs also may reflect effects of XX or XY chromosome complement. Methods We measured numbers of HSPCs in age-matched male and female mice and in Four Core Genotype (FCG) mice, which isolate the effects of chromosome complement (XX or XY) and gonadal sex (M or F), across the lifespan. To assess the relative fitness of LT-HSCs, we generated competitive bone marrow (BM) chimeras comparing male and female LT-HSCs transferred to male or female hosts, or LT-HSCs from FCG mice with identical gonadal sex, but different chromosome complement. After 4 mos, we measured their contribution to HSPCs and mature immune cells. Results Sexually mature males have more HSPCs in BM than females, with a minor elevation of LT-HSCs and ST-HSCs and a significant increase in lymphoid-biased MPP4s. In mixed BM chimeras, male LT-HSC-derived cells dominate in BM, spleen, and lung in both female and male hosts, indicating a superior intrinsic capacity to engraft regardless of the steroid environment. Analyses of FCG mice showed that HSPCs were primarily regulated by gonadal sex pre- and post-puberty, with a small contribution of chromosome complement for some subsets. Mixed competitive LT-HSC BM chimeras generated with XXF and XYF into females or XXM and XYM into males showed that sex chromosome complement alone had little effect on engraftment. Conclusion Male HSPCs have a superior cell intrinsic fitness, which may impact immune system regeneration in chronic inflammation, infection, and BM transplantation. Funding Source Oklahoma Center for Adult Stem Cell Research, AAI Careers in Immunology Fellowship Topic Categories Hematopoiesis and Immune System Development (HEM)