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

Hematopoietic stem cells (HSCs) adapt to organismal blood production needs by balancing self-renewal and differentiation, adjusting to physiological demands and external stimuli. Although sex differences have been implicated in differential hematopoietic function in males versus females, the mediators responsible for these effects require further study. Here, we characterized hematopoiesis at a steady state and during regeneration following hematopoietic stem cell transplantation (HST). RNA sequencing of lineage(-) bone marrow cells from C57/Bl6 mice revealed a broad transcriptional similarity between the sexes. However, we identified distinct sex differences in key biological pathways, with female cells showing reduced expression of signatures involved in inflammation and enrichment of genes related to glycolysis, hypoxia, and cell cycle regulation, suggesting a more quiescent and less inflammatory profile compared with male cells. To determine the functional impacts of the observed transcriptomic differences, we performed sex-matched and mismatched transplantation studies of lineage(-) donor cells. During short-term 56-day HST recovery, we found a male donor cell proliferative advantage, coinciding with elevated serum TNF-α, and a male recipient engraftment advantage, coinciding with increased serum CXCL12. Together, we show that sex-specific cell responses, marked by differing expression of pathways regulating metabolism, hypoxia, and inflammation, shape normal and regenerative hematopoiesis, with implications for the clinical understanding of hematopoietic function.

15-PGDH regulates hematopoietic and gastrointestinal fitness during aging.

Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cells' regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness.