HGF and c-Met signaling in tissue repair and organ regeneration
Tyrosine kinase receptors are a family of cell membrane receptors whose activities are important in both physiological and pathological processes including tissue protection, regeneration, angiogenesis, and fibrosis. Modulation of tyrosine kinase receptor activity represents a major tool in the discovery of new therapeutics for the treatment of major diseases.
The naturally-occurring cytokine hepatocyte growth factor (HGF), also known as scatter factor, is active in numerous tissues throughout the body, participating in the regulation of angiogenesis, organogenesis, tissue repair and neural induction. HGF induces random movement ("scatter") in epithelial cells as well as dissociation, migration, and invasion of cells through the extracellular matrix in vivo. HGF is mitogenic (induces proliferation) in many normal cell types, including epithelial cells, vascular endothelial cells, and melanocytes. HGF is a morphogen that induces transition of epithelial cells into a mesenchymal (connective tissue-type) morphology and formation of branched tube-like structures; these cellular responses reflect this cytokine's role in organogenesis and tissue repair. HGF is cytoprotective by virtue of its anti-apoptotic activity and exerts anti-fibrotic effects by opposing TGFβ1-Smad signaling. Each of these biological effects exerted by HGF is triggered by stimulating its cell surface receptor c-Met, with concomitant activation of downstream effector pathways.
Both HGF and Angion’s HGF mimetic, BB3, by interacting with and dimerizing the extracellular domain of c-Met, induce tyrosine kinase (TK) activity and transduce intracellular signaling through a cascade of mediators (ovals). This results in upregulation of several transcription factors producing altered cellular physiology (pale blue boxes) with salutary effects on disease endpoints (dark blue boxes).
Moreover, these effects of HGF/c-Met pathway activation translate to organoprotective and organoreparative effects. Beneficial effects of HGF (protein or DNA) administration have been recorded in animal models of acute renal, myocardial, cerebral and hepatic ischemic or toxic injury. HGF administration also exhibits significant benefit in chronic organodegenerative models characterized by structural remodeling, fibrosis, collagen deposition, and progressive organ dysfunction.
An important prediction that emerges from the study of HGF and c-Met is that agonists of c-Met (also called HGF mimetics) should promote tissue repair and organ regeneration in two ways: first, as a prophylactic, by protecting healthy cells from both necrotic and apoptotic death; and second, as a therapeutic, by promoting appropriate cell proliferation and migration needed for repair of pre-existing tissue injury. A vast amount of literature indicates that HGF and its mimetics (proteins, peptides and antibodies) can be used as therapeutics in (1) protecting major organs (including the liver, kidney, lung, heart, brain, and spinal cord) from injury, and (2) reducing fibrosis in the liver, kidney, lung, and heart.
An important feature of HGF mimetics as a class is that they possess therapeutic activities against apoptotic cell death and fibrosis and stimulate tissue regeneration. This feature is important in that several diseases, such as fibrosis of the liver, lung, and kidney, and cardiovascular disease and peripheral vascular disease, develop via more than one of these mechanisms.
