635 Mechanical stretch mobilizes Lgr6+ stem cells to drive skin growth

Abstract

After injury, a timely inflammatory response that involves the recruitment of blood-derived circulating monocytes is essential for tissue repair. Once in the wound bed, these cells differentiate into macrophages during the inflammatory phase, a process that goes awry during aging in chronic non-healing wounds. Cell differentiation is a highly energydemanding process, and metabolic substrates present in the wound bed niche are important for the wound healing outcome. We previously demonstrated that dermal adipocytes release fatty acids into wound beds after injury to promote inflammation, yet the function of adipocyte-derived fatty acids in the initiation of the inflammatory response after injury is not known. To unveil the role of adipocytes as providers of fatty acids used to fuel the metabolic requirements of immune cell differentiation, we set out to evaluate their role on monocyte to macrophage differentiation in the skin wound bed. Here, we utilize in vivo mouse models of skin injury and metabolic assays to reveal that monocytes utilize fatty acids to fuel metabolic programs that induce macrophage differentiation. We show that extracellular vesicles (EVs) loaded with lipids are actively taken up by monocytes in vitro and in mice in vivo. Using realtime respirometry, we show that these fatty acids activate the b-oxidation metabolic pathway in monocytes and its inhibition leads to the abrogation of macrophage differentiation. Furthermore, we show that with age, not only adipocyte-derived EV production was impaired, but more importantly, these particles were less effective in rewiring monocyte metabolism towards oxidative phosphorylation. In summary, our findings reveal an essential adipocyte-monocyte metabolic axis that controls inflammation in the wound bed niche.