Sex-dependent niche responses modulate steady-state and regenerative hematopoiesis

Hematopoietic stem cells (HSCs) adapt to organismal blood production needs. While it has been established that sexual dimorphism drives differential hematopoietic function in males vs. females, the mediators responsible for these effects remain unclear. Here, we characterize hematopoiesis in male and female mice at steady state and during regeneration following hematopoietic stem cell transplantation (HST). We found that steady-state males possessed greater bone marrow (BM) hematopoietic stem and progenitor cell (HSPC) populations and varied in frequency for stromal populations. PCR analysis from stromal CD45(-)-purified BM cells demonstrated alterations in niche genes, including Ptn, IL6, Angpt1, Vcam1, and Spp1, together suggesting the male microenvironment is primed for HSC differentiation and mobilization. RNA sequencing of BM lineage(-) cells revealed differential expression of genes, like Hif1a and Aldh1, and corresponding cellular pathways—including those involving reactive oxygen species, oxidative phosphorylation, and Tnf-a signaling via NF-κB—underscoring male lineage(-) cells as more inflammatory and proliferative. To determine the functional outcomes of steady-state transcriptional differences we performed sex-matched and mismatched transplantation studies of lineage(-) donor cells into male and female recipients. We demonstrated a role for TNF-a-driven proliferation of male donor cells and Cxcl12-mediated homing into male recipients during short-term 56-day HST recovery. Serial transplantation of lineage(-) cells suggested the male short-term proliferative advantage may precede long-term disadvantages of inflammation-induced exhaustion. We show that sex-specific cellular and molecular signaling, marked by differing expression of niche factors and inflammatory mediators, shapes normal and regenerative hematopoiesis, with implications for the fundamental and clinical understanding of hematopoietic function.