Abstract

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.