HGFA Is an Injury-Regulated Systemic Factor that Induces the Transition of Stem Cells into G_Alert

The activation of quiescent stem cells into the cell cycle is a key step in initiating the process of tissue repair. We recently reported that quiescent stem cells can transition into G_Alert, a cellular state in which they have an increased functional ability to activate and participate in tissue repair. However, the precise molecular signals that induce G_Alert in stem cells have remained elusive. Here, we show that the injury-induced regulation of hepatocyte growth factor (HGF) proteolytic processing via the systemic protease, hepatocyte growth factor activator (HGFA), stimulates G_Alert in skeletal muscle stem cells (MuSCs) and fibro-adipogenic progenitors (FAPs). We demonstrate that administering active HGFA to animals is sufficient to induce G_Alert in stem cells throughout the body and to significantly accelerate the processes of stem cell activation and tissue repair. Our data suggest that factors that induce G_Alert will have broad therapeutic applications for regenerative medicine and wound healing.