Studies on Tissue Morphogenesis, Organogenesis and Repair by HGF

HGF是我们实验室发现并克隆的一种促肝因子。我们积累的证据表明，HGF具有多性功能，如有丝分裂、运动发生、形态发生等。基于这些背景，我们假设HGF可能作为间质衍生因子在形态发生和组织修复中发挥重要作用。为了验证我们的假设，我们在最近3年集中研究了HGF的生理作用。通过急性和慢性疾病的动物模型，我们证明了HGF是一种必不可少的内在修复因子：在损伤模型中，内源性HGF在组织破坏发生后急剧增加。重要的是，抗hgf IgG强烈抑制实质细胞（包括肝细胞、肾小管细胞、肺细胞、肺泡细胞等）的再生反应；从而表明内源性HGF是体内组织再生的关键参与者。相反，补充外源性HGF导致组织再生加速，在实质损伤（包括肝硬化、肾纤维化、肺病和心脏病等）中表现得更为明显。在肿瘤恶性形成过程中，HGF参与肿瘤侵袭和血管生成。因此，我们制备了NK4/HGF作为HGF的拮抗剂，发现NK4可使肿瘤的恶性程度最小化，同时抑制肿瘤的转移、侵袭和血管生成。有趣的是，NK4对几种类型的血管生成表现出广泛的抗血管生成活性，不依赖于hgf介导的内皮生长。通过这些体内和体外研究，我们获得了证据，证明NK4可能通过抗侵入性和抗血管生成谱对肿瘤恶性肿瘤的最小化有用。最后，我们分析了LIMK激酶（LIMK）激活的调控系统：我们发现LIMK1在Rac和Pac级联下游的调控下激活，而LIMK2在Rho和ROCK流下激活。此外，我们发现LIMK2在体内精子发生中起着关键作用，使用LIMK2基因靶向小鼠。通过这些实验，我们得出结论，HGF（可能还有它的家族分子）在形态发生和组织修复中起着关键作用。少

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