Sex dimorphism in the bone marrow niche regulates hematopoietic engraftment via sexspecific Kdm5c-Cxcl12 signaling

ABSTRACT: The bone marrow (BM) niche is critical in regulating hematopoiesis, and sexual dimorphism in hematopoiesis and immunocompetence is observed in both mice and humans. Beyond hormonal influences, the mechanisms underlying sexual differences in the BM niche and their impact on hematopoiesis are not well understood. Here, we show that male mice exhibit a higher abundance of leptin-receptor-expressing mesenchymal stromal cells (LepR-MSCs) compared to female mice. Through sex-mismatched co-culture and BM transplantation experiments, we find that the male BM niche provides superior support for in vitro colony formation and in vivo hematopoietic engraftment. Notably, the co-transplantation of male stromal cells significantly enhances engraftment in female recipients. Single-cell RNA sequencing reveals sex-specific differences in cellular composition and gene expression profiles within BM stromal cells, with MSCs being the predominant population, particularly in the male BM stroma. Mechanistically, we identify lower expression of the X-linked lysine H3K4 demethylase, Kdm5c, in male MSCs, leading to increased levels of Cxcl12. In a mouse model with MSC-specific Kdm5c knockout, the reduction of Kdm5c in female MSCs enhances MSC quantity and function, ultimately improving engraftment to the male level. This suggests that Kdm5c may play a role in driving sexual dimorphism in the BM niche and hematopoietic regeneration. Our study unveils a sex-dependent mechanism governing BM niche regulation and its impact on hematopoietic engraftment. The finding offers potential implications for enhancing BM transplantation efficacy in clinical settings by harnessing the resource of male MSCs or targeting Kdm5c.

ORGANISM(S): Mus musculus

PROVIDER: GSE267695 | GEO | 2025/01/30

REPOSITORIES: GEO