Studies on Tissue Morphogenesis, Organogenesis and Repair by HGF

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HGF was found and cloned as a hepatotropic factor in our laboratory : We have accumulated evidence that HGF has pleotropic functions such as mitogenesis, motogenesis, morphogenesis and so on. Based on these backgrounds, we hypothesized that HGF plays an important role for morphogenesis and tissue repair, possibly as a mesenchyme-derived factor.To test our hypothesis, we focused during the recent 3 years, on physiological roles by HGF. Using animal models for acute and chronic diseases, we demonstrated that HGF is an essential intrinsic repair factor : In the injury models, endogenous HGF dramatically increased after onset of tissue destruction. Of importance, an anti-HGF IgG strongly suppressed regenerative responses by parenchymal cells (including liver hepatocytes, renal tubular cells lung; alveolar cells etc...); thereby suggesting that endogenous HGF is a key player for eliciting tissue regeneration in vivo. Conversely, supplement of exogenous HGF led to acceleration of tissue repa … More ir in parenchymal injuries (including liver cirrhosis, renal fibrosis, lung and heart diseases and so on).In tumor malignant formation, HGF is participated in tumor invasion and angiogenesis. Thus we prepared NK4/HGF as an antagonist for HGF and found that NK4 minimized tumor malignancy, accompanied with repressed tumor metastasis, invasion and angiogenesis. Of interest, NK4 shows broad anti-angiogenetic activities toward several types of angiogenesis, independent on HGF-mediated endothelial growth. Through these in vivo and in vitro studies, we obtained evidence that NK4 is useful for minimization, of tumor malignancy, possibly through anti-invasive and anti-angiogenetic profiles.Finally, we analyzed a regulation system for activation of LIM-kinase (LIMK) : We found that LIMK1 is activated under regulations under down-streams of Rac and Pac cascades while LIMK2 activation occurs under Rho and ROCK streams. Furthermore, we found that LIMK2 plays a critical role in spermatogenesis in vivo, using a gene-targeted mice for LIMK2.Throughout these experiments, we conclude that HGF (and possibly, its family molecules) are critically involved in morphogenesis and tissue repair. Less