Sex dimorphism in bone marrow niche and its effect on hematopoietic transplantation

About This Grant

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is an important treatment for blood diseases and immune disorders. Donor-recipient compatibility, particularly sex matching, is one of the determining factors for HSCT success. Sex dimorphism in hematopoiesis and immunocompetence has been documented in both mice and humans. However, the sex variations in the bone marrow (BM) niche, their impact on hematopoiesis and HSCT, and the underlying mechanisms remain largely known. Our preliminary work showed that male mice have more mesenchymal stromal cells (MSCs) than females. Through sex-mismatched co-culture and transplantation experiments, we found that the male BM niche provides better support for colony formation in vitro and hematopoietic engraftment in vivo. Single-cell RNA sequencing identified the sex-specific changes in cell composition and molecular differences between male and female niche. Mechanistically, we found that a sex chromosome-linked histone demethylase gene, Kdm5c, contributes to the differential expression of Cxcl12 between male and female stromal cells. Moreover, sex- and MSC-specific reduction in Kdm5c expression increases the hematopoietic engraftment in HSCT. We hypothesize that sex dimorphism in the BM niche regulates hematopoietic engraftment in HSCT via sex-specific Kdm5c-Cxcl12 signaling. Aim 1 is to determine the cellular mechanisms by which Kdm5c regulates sex dimorphism in the BM niche. Aim 2 is to determine the molecular mechanisms by which Kdm5c-Cxcl12 signaling contributes to sex differences in the BM niche and hematopoietic engraftment. Aim3 is to determine the therapeutic value of BM niche sex dimorphism in HSCT. The findings advance our understanding of sex dimorphism in the BM niche and the underlying regulatory mechanism and provide the therapeutic implication for improving HSCT in the clinic.