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

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.