Mast Cell Derived Histamine Negatively Regulates Hematopoiesis

Mast cells (MCs) are well known for their roles in immunity, but their influence on hematopoietic stem cell (HSC) regulation remains poorly defined. Here, we identify MC-derived histamine as a suppressor of hematopoiesis. MC-deficient "SASH" mice exhibited increased bone marrow HSC frequency, a transcriptional quiescence signature, and resistance to myeloablative chemotherapy, associated with niche remodeling, including increased HSC-supportive stromal populations and elevated maintenance factor expression, and improved engraftment of wild-type donor cells. Reciprocal transplants showed this phenotype is driven by the recipient niche rather than an HSC-intrinsic property, and MC-derived secretory factors were directly sufficient to suppress HSCs in vitro and in vivo. Pharmacologic H1 receptor blockade with cetirizine, an FDA-approved inverse agonist, phenocopied the SASH model, expanding HSCs and enhancing both early recovery and long-term reconstitution in transplant settings, while exogenous histamine reversed the SASH phenotype. Supporting clinical relevance, electronic health record analysis revealed that antihistamine use was associated with elevated white blood cell counts in humans. These findings establish mast cell-derived histamine as a suppressor of hematopoiesis and suggest that H1R antagonism may offer a tractable strategy to enhance hematopoietic regeneration. Teaser Abstract: Mast cell-derived histamine restrains hematopoietic stem cell activity by shaping the bone marrow niche. Blocking histamine signaling with the FDA-approved antihistamine cetirizine expands the stem and progenitor pool and accelerates hematopoietic recovery after transplant, pointing to a repurposable strategy for boosting blood regeneration in patients.