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

Abstract

SUMMARY 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 GAlert, a cellular state in which they have an increased functional ability to activate and participate in tissue repair. However, the precise molecular signals which induce GAlert 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 GAlert in skeletal muscle stem cells (MuSCs) and fibro-adipogenic progenitors (FAPs). We demonstrate that administering active HGFA to animals is sufficient to induce GAlert 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 GAlert will have broad therapeutic applications for regenerative medicine and wound healing.

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

“…Under those conditions, it relayed a signal to quiescent stem cells in non‐injured tissues, inducing their transition into a primed G Alert state through HGF/SF‐MET‐mTORC1 signaling (Fig. a) . Whereas this observation was made in striated muscle stem cells and fibro‐adipogenic progenitors, other somatic stem cells such as mesenchymal, epidermal and hematopoietic stem cells also express MET, and accordingly, these stem cells may respond to HGFA in a similar fashion.…”

Adult stem cells and regenerative medicine—a symposium report

“…While these cells are still quiescent, they are primed to respond more rapidly and regenerate tissue more quickly after a subsequent injury than in uninjured animals. This alert state is regulated by hepatocyte growth factor–mediated activation of mTORC1 signaling …”

“…This alert state is regulated by hepatocyte growth factor-mediated activation of mTORC1 signaling. 27,28 Rando also proposed that aging can cause MuSCs to adopt a deeper state of quiescence. MuSCs from older animals take longer to break quiescence than those from younger animals.…”

Wound‐induced cell proliferation during animal regeneration

“…Consistent with these varied and major roles, the mTOR pathway has been implicated in a number of biological processes, including regeneration (Figure ). In mammals, mTOR was found to be required for cell proliferation in muscle regeneration at both local and systemic levels (Figure ) (Han, Tong, Zhu, Ma, & Du, ; Rodgers et al, ; Rodgers, Schroeder, Ma, & Rando, ; Zhang, Liang, Shan, Jiang, & Deng, ), and in liver regeneration (Fouraschen et al, ; D. X. Zhang et al, ). In planarian regeneration, mTOR does not appear to be involved in wound healing or in injury‐induced cell death, but it is required for induction of IIHP (González‐Estévez et al, ; Tu et al, ), consistent with its role as a downstream integrator of the wound response (Figure ).…”

“…In addition to activating muscle satellite cells to proliferate upon injury in mice (Miller et al, ; Tatsumi, Anderson, Nevoret, Halevy, & Allen, ), HGF also triggers systemic proliferation, that is, satellite cells located at great distances from the site of injury show elevated levels of proliferation. It has been proposed that hepatocyte growth factor activator (HGF‐A) activated by Thrombin locally at the wound site enters the circulatory system, thereby activating HGF system‐wide, directing cells to an “alert” state via the mTOR pathway (Rodgers et al, , ). A systemic IIHP also has recently been demonstrated in axolotls—in addition to increased proliferation in the amputated limb, number of dividing cells increased in the contralateral limb and in other tissues including heart, liver and spinal cord (Johnson et al, ).…”