Latexin regulates sex dimorphism in hematopoiesis via gender-specific differential expression of microRNA 98-3p and thrombospondin 1

Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate to all blood cell types. HSCs and their differentiated progeny show sex/gender differences. The fundamental mechanisms remain largely unexplored. We previously reported that latexin (Lxn) deletion increased HSC survival and repopulation ca-pacity in female mice. Here, we find no differences in HSC function and hematopoiesis in Lxn knockout (Lxn-/-) male mice under physiologic and myelosuppressive conditions. We further find that Thbs1, a down-stream target gene of Lxn in female HSCs, is repressed in male HSCs. Male-specific high expression of micro -RNA 98-3p (miR98-3p) contributes to Thbs1 suppression in male HSCs, thus abrogating the functional effect of Lxn in male HSCs and hematopoiesis. These findings uncover a regulatory mechanism involving a sex -chromosome-related microRNA and its differential control of Lxn-Thbs1 signaling in hematopoiesis and shed light on the process underlying sex dimorphism in both normal and malignant hematopoiesis.

Automated summary

Hematopoietic stem cells (HSCs) have sex differences in their function and hematopoiesis. Deletion of latexin (Lxn) gene promoted HSC survival and repopulation capacity in female mice, but showed no effect in male mice. Male-specific high expression of microRNA 98-3p (miR98-3p) contributed to the suppression of Thbs1 gene in male HSCs, leading to the abrogation of Lxn's functional effect on HSCs and hematopoiesis. These findings reveal a regulatory mechanism involving sex-chromosome-related microRNA and its differential control of Lxn-Thbs1 signaling in hematopoiesis, contributing to the understanding of sex dimorphism in hematopoiesis.