Campanelli, J. | bioRxiv Science

bioRxiv2022

Sex-specific niche signaling contributes to sexual dimorphism following stem cell transplantation

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 PointsO_LIMale and female mice display altered kinetics of regeneration following HST due to unique niche factors in hematopoietic compartments. C_LIO_LIExogenous steroid sex hormones uniquely regulate the pool of hematopoietic stem and progenitor cells and may impact transplantation outcomes. C_LI

immunology↗

bioRxiv2022

Inactivating Mast Cell Function Promotes Steady-State and Regenerative Hematopoiesis

Hematopoietic stem cells (HSCs) are essential for generating all blood cell types and maintaining immune function and oxygen transport. This requires tight regulation of self-renewal, differentiation, and quiescence, driven by intrinsic and extrinsic signals. While the influence of many HSC progeny on HSC decisions are recognized, the role of mast cells (MCs) remain understudied. MCs are known for their immunomodulatory functions through the secretion of factors such as histamine and could offer new insights into HSC regulation. In this study, we describe a novel role for MC-derived histamine in modulating HSC behavior. We observed that genetically MC-deficient "SASH" mice exhibit increased hematopoietic output and bone marrow (BM) HSCs, characterized by an enhanced quiescent signature that increases resistance to myeloablative chemotherapy. The SASH microenvironment also contained increased frequencies of HSC-supportive cell types and expression of genes conducive to HSC maintenance, which together accelerated HSC engraftment when wild-type BM was transplanted into SASH recipients. Moreover, we found lower serum histamine levels in SASH mice, and that the enhanced hematopoietic phenotype observed in these mice could be reversed by administering exogenous histamine. Subsequent experiments with FDA-approved antihistamines in wild-type mice revealed that cetirizine, an H1R inverse agonist, notably increased HSC frequency in the BM. Overall, our findings implicate MCs are negative regulators of HSC function. This lays the groundwork for future studies to elucidate the underlying mechanisms and explore the therapeutic potential of modulating histamine signaling to promote hematopoiesis.

immunology↗