Fibroadipogenic Progenitors contribute to microvascular repair during skeletal muscle regeneration

Skeletal muscle injury results in a disruption of the muscle bed vascular network. A local source of vascular progenitors during muscle regeneration has not been clearly identified. Fibroadipogenic progenitors (FAPs) are required for proper regeneration, however they can also directly contribute to fibrotic and fatty infiltration in response to chronic muscle injury and muscle disease. We show here that acute muscle injury leads to hypoxia and glucose deprivation, triggering FAP proliferation and differentiation into endothelial cells in vitro and in vivo. In response to glucose deprivation, FAPs down regulate fibrotic and fat associated genes and acquire an endothelial cell fate, which is dependent upon mTORC2-HIF2-eNOS pathway. These findings bring new insights into the mechanisms of vascular regeneration during muscle regeneration and define a highly plastic resident progenitor population that responds to oxygen/glucose-deprivation induced cell stress by promoting an endothelial cell fate.