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Hematopoietic stem cell (HSC) transplantation (HST) is a curative treatment for many hematopoietic cancers and bone marrow (BM) disorders but is currently limited by numerous complications including a lengthy recovery period, prolonged neutropenia resulting in severe infections and bleeding, and a high incidence of graft vs. host disease (GVHD). While clinical studies have demonstrated that sex mismatch, notably male recipients with female donor cells, results in increased risk of GVHD (likely due to male recipient minor histocompatibility antigens targeted by donor female T-cells 1), increased non-relapse mortality, and decreased overall survival, the mechanisms underlying sex-determinants on hematopoiesis and post-transplant recovery are not clear. In this manuscript we have identified: 1) unique expression of hematopoietic niche factors in the BM and spleens of male and female mice, 2) altered kinetics of hematopoietic reconstitution following transplantation when male vs. female BM is used as the donor cell source, 3) a sex-specific role for the recipient niche in promoting post HST recovery, and 4) a dose-dependent role for exogenous sex hormones in maintaining hematopoietic stem and progenitor cells (HSPCs). Taken together, these data demonstrate that sex-specific cellular and molecular signaling occurs during hematopoietic regeneration. Further identifying novel sex-dependent determinants of regeneration following transplantation will not only enhance understanding of steady state versus regeneration hematopoiesis but may also reveal unique (and potentially sex-specific) therapeutic targets to accelerate hematologic recovery.Key PointsMale and female mice display altered kinetics of regeneration following HST due to unique niche factors in hematopoietic compartments.Exogenous steroid sex hormones uniquely regulate the pool of hematopoietic stem and progenitor cells and may impact transplantation outcomes.

Deeper understanding of the cellular and molecular pathways regulating hematopoiesis is critical to maximize the therapeutic potential of hematopoietic stem cells (HSCs) in curative procedures including hematopoietic stem cell transplantation (HST). We have recently identified mast cells (MCs) as therapeutically-targetable components of the HSC niche. Here, we demonstrate that mice lacking MCs display peripheral neutrophilia, expansion of bone marrow (BM) HSC populations, resistance to repeated 5-fluorouracil (5-FU) administration, and a BM genetic signature primed for hematopoietic proliferation. MC deficiency functionally altered both the hematopoietic and the stromal compartment of the BM as hematopoietic reconstitution was accelerated in wildtype mice that received MC deficient BM and in MC deficient recipients that received wildtype BM. Finally, we demonstrate that mice treated at steady state with the MC stabilizing agent ketotifen exhibit increased BM cellularity as well as expansion of phenotypic HSC populations. This work provides novel mechanistic rationale to explore mast cells as a target to enhance human BM transplants. Additionally, the potential of repurposing FDA approved mast cell targeting therapies to promote hematopoietic regeneration may provide well-tolerated treatment strategies at a fraction of the cost and development time.