HGF is produced and secreted from nonparenchymal cells (such as resident fibroblasts, infiltrated macrophages as well as endothelial cells), whereas c-Met is mainly expressed on the side of parenchymal areas (9,10,17) (Fig. 1). The c-Met level is upregulated in response to injurious stresses and activated specifically in diseased tissues (10,28). This mesenchyme-to-parenchyme humoral signal(s) is essential for organ tissue repair, development as well as organ protection.
In injured sites of parenchymal organs, HGF elicits mitogenic and motogenic activities in order to restore the integrity of the parenchymal components (9,10,17) (Fig. 1, bottom). HGF has a morphogenic function toward replicated cells to create tubular duct formation via controlling cell arrangement and polarity (9,10,27). Furthermore, HGF controls metabolic events in parenchymal epithelial cells, for example HGF stimulates production and secretion of albumin in hepatocytes (29) and of insulin in pancreatic P-cells (30), hence there is a role of HGF for inducing and sustaining homeostasis within physiological limits. In repair processes, vascular endothelial cell proliferation is a prerequisite for delivery of oxygen and nutrition to injured sites. Because HGF is a potent mitogen for vascular endothelium (31,32), its activity contributes to maintain aerobic conditions in injured sites.
The multiple functions mediated by HGF/c-Met coupling are critical also for organogenesis in an embryonic stage. We prepared c-Met-deficient zenopus embryo, using a c-Met dominant negative mutant, and showed that HGF signal is required for development of the kidney, liver, and intestines (33). During lung development, branching tubulogenesis becomes evident in parenchymal areas at E13.5 d of the mouse embryo, and is associated with increased HGF expression in meschenchymal areas (34). When this HGF activity is neutralized by an antibody specific to HGF, branching tubulogenesis is diminished, hence HGF plays a key role for lung development (34). Furthermore, studies with the c-Met-deficient mouse strain delineated an essential role of HGF/c-Met signaling in placental, hepatic, and muscular development (35-37). Given that meschenchymal stromal cells (such as fibroblasts) are a major source of HGF, HGF/c-Met axis confers a mesenchyme-to-parenchyme system for organ development.
In addition to such morphogenic bioactivities, HGF has a protective function in a variety of organs (10,17,38). In fact, HGF is anti-apoptotic and completely blocks the onset of fulminant hepatitis (39), myocardial infarction (40), and ischemic neuron cell death in rodents (41). Inducing anti-apoptotic signals (such as Bcl-xL/Bcl-2 and Bag-1) (39-43) as well as sequestration of Fas by activated c-Met (44) is involved in this anti-apoptotic process. such protective effects are now widely demonstrated in numerous organs during parenchymal injury (45-47). Overall, HGF is identified as a key ligand not only to induce regenerative responses but also to reduce parenchymal damage.
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