Mast Cell Derived Histamine Negatively Regulates 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. Overall design: This study investigated the transcriptional differencees between bulk bone marrow and lineage depleted bone marrow between WT (c57 mice) and mast cell deficiient SASH mice