Hepatocyte growth factor activator (HGFA): pathophysiological functions in vivo

Prior research has established that hepatocyte growth factor (HGF) is essential for tissue morphogenesis and regeneration through the MET receptor. However, the mechanisms regulating HGF activation in vivo remain partially understood. Macrophage-stimulating protein (MSP) signaling via RON is also known to influence macrophage function and wound healing. This gap motivated further investigation into the role of HGF activator (HGFA), a serine protease that activates both HGF and MSP. No prior work had resolved how HGFA's pericellular activity influences these cytokines' functions in vivo. HGFA is primarily produced by the liver and circulates as a zymogen. Local production by epithelial or tumor cells has been observed, but its physiological significance remains unclear. The role of HGFA in tissue injury and regeneration is not fully characterized. This uncertainty drove the need to explore HGFA's contributions to tissue repair and disease progression.

This study aimed to clarify the physiological and pathophysiological roles of HGFA in vivo. The specific problem addressed is the lack of understanding about how HGFA regulates HGF and MSP activation in tissue injury and regeneration. The motivation stems from the observation that HGFA is activated in response to tissue damage and may influence macrophage recruitment and epithelial repair. The study sought to determine whether HGFA's activity is essential for normal tissue function or if other proteases can compensate. The researchers focused on the role of HGFA in epithelial regeneration and macrophage signaling. They also examined whether HGFA contributes to fibrotic lung diseases or cancer progression. The goal was to distinguish between HGFA's compensable and non-compensable functions in vivo. The study's findings could inform therapeutic strategies targeting HGFA activity.

The researchers used a combination of genetic and biochemical approaches to study HGFA's functions. They generated HGFA-knockout mice to assess the protease's role in development and tissue repair. Tissue injury models were employed to evaluate HGFA's activation in response to damage. Plasma and tissue samples were analyzed to determine HGFA's expression and activation status. Immunohistochemistry and in situ hybridization were used to locate HGFA in tissues. The study also examined the effects of HGFA deficiency on macrophage recruitment and epithelial regeneration. Histological and functional assays were performed to assess tissue repair outcomes. The researchers compared wild-type and knockout mice to identify HGFA-specific effects. These methods allowed the team to trace HGFA's contributions to physiological and pathological processes.

HGFA-knockout mice showed normal development, indicating that other proteases can compensate in most physiological settings. However, in injured tissues, HGFA deficiency led to impaired regeneration of mucosal epithelium. The study found that HGFA is essential for macrophage recruitment in response to tissue damage. Insufficient HGFA activity was linked to delayed wound healing and fibrotic lung disease progression. In tumor models, HGFA overexpression was associated with increased cancer progression. The researchers observed that HGFA activates both HGF and MSP in vivo. Local production of pro-HGFA by epithelial and stromal cells was confirmed. The study also showed that HGFA is activated in response to tumor growth. These findings suggest that HGFA's activity is tightly regulated and context-dependent.

The authors concluded that HGFA's role in normal development is largely compensable by other proteases. However, in injured tissues, HGFA is necessary for macrophage recruitment and epithelial regeneration. The study showed that insufficient HGFA activity impairs mucosal repair and may contribute to fibrotic lung diseases. Excessive HGFA activity may promote tumor progression. These findings suggest that HGFA's activity is context-dependent and regulated in vivo. The authors propose that HGFA's pericellular activity is a key factor in regulating HGF and MSP signaling. The study highlights the importance of HGFA in tissue injury and repair. The findings support the idea that HGFA is a potential target for therapeutic interventions in regeneration and cancer.