Sex dimorphism in the mouse bone marrow niche regulates hematopoietic engraftment via sex-specific Kdm5c/Cxcl12 signaling

The bone marrow (BM) niche is critical in regulating hematopoiesis, and sexual dimorphism and its underlying mechanism in BM niche and its impact on hematopoiesis are not well understood. We show that male mice exhibited a higher abundance of leptin-receptor-expressing mesenchymal stromal cells (LepR-MSCs) compared to female mice. Sex-mismatched co-culture and BM transplantation showed that the male BM niche provided superior support for in vitro colony formation and in vivo hematopoietic engraftment. The co-transplantation of male stromal cells significantly enhanced engraftment in female recipients. Single-cell RNA sequencing revealed that the lower expression of the X-linked lysine H3K4 demethylase, Kdm5c, in male MSCs led to the increased expression of Cxcl12. In MSC-specific Kdm5c knockout mouse model, the reduction of KDM5C in female MSCs enhanced MSC quantity and function, ultimately improving engraftment to the male level. Kdm5c thus plays 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.