Hepatocyte growth factor induces angiogenesis in injured lungs through mobilizing endothelial progenitor cells

Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 12/2004; 324(1):276-80. DOI: 10.1016/j.bbrc.2004.09.049
Source: PubMed


Circulating endothelial progenitor cells (EPCs) play a pivotal role in angiogenesis. Hepatocyte growth factor (HGF) is known to induce proliferation and motility in endothelial cells, and to play a role in mitogenic and morphogenic actions. However, the role of HGF in EPC mobilization has not been clearly described yet. We investigated the effect of HGF on mobilizing EPCs and on angiogenesis in elastase-induced lung injury. HGF significantly increased the triple-positive (Sca-1(+), Flk-1(+), and c-kit(+)) fraction in peripheral mononuclear cells in mice. The bone marrow-derived cells were recruited into the injured lungs, where they differentiated to capillary endothelial cells. HGF induced proliferation of both bone marrow-derived and resident endothelial cells in the alveolar wall. In conclusion, the present study suggests that HGF induces EPC mobilization from the bone marrow and enhances the proliferation of endothelial cells in vivo. These complex effects induced by HGF orchestrate pulmonary regeneration in emphysematous lung parenchyma.

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Available from: Hiroshi Kubo
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    • "HGF has multiple biological properties, including mitogenic, morphogenic (Matsumoto and Nakamura, 1992; Boros and Miller, 1995; Ricci et al., 1999), and anti-apoptotic activities in a variety of cell types (Kosai et al., 1999; Liu, 1999). HGF has great potential as an anti-inflammatory, anti-fibrosis, anti-apoptotic (Kellermann et al., 2009) and angiogenic agent (Ishizawa et al., 2004). These cellular effects of HGF may increase the therapeutic effect of MSCs for the treatment of liver failure. "
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    ABSTRACT: Fibrosis is a common end stage for a variety of liver diseases, including most chronic liver diseases, and results from an imbalance between collagen deposition and degradation. Mesenchymal stem cells (MSCs) have the ability to migrate into fibrotic livers and differentiate into hepatocytes. Hepatocyte growth factor (HGF) has potent anti-apoptotic and mitogenic effects on hepatocytes during liver injury and plays an essential role in the development and regeneration of the liver. In this study, human HGF-overexpressing human umbilical cord blood-derived MSCs (hHGF-HUCB-MSCs) were prepared using the pMEX Expression System, and the upregulation of hHGF expression was confirmed by RT-PCR and ELISA. HGF expressed by hHGF-HUCB-MSCs exerted a stimulatory effect on hepatocyte proliferation in vitro. hHGF-HUCB-MSCs were transplanted to investigate the therapeutic effects of these cells on carbon tetrachloride (CCL4 )-induced liver fibrosis in a rat model. After 4 weeks of cell treatment once per week with 2 × 10(6) cells, biochemical analysis of the serum and histopathological analysis of the liver tissue were performed. The results of the biochemical analysis of the serum showed that the hHGF-HUCB-MSC-treated group exhibited increases in the levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, indicating the improvement of liver function. The histopathological analysis showed that the hHGF-HUCB-MSC-treated group exhibited a reduction in the density of collagen fibers. These results suggest that hHGF-HUCB-MSCs can enhance liver regeneration and could be potentially useful for the treatment of patients with liver fibrosis or cirrhosis.
    Full-text · Article · Jan 2014 · Cell Biology International
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    • "HGF mRNA levels are elevated in damaged lung tissue82, 91, and HGF protein levels are increased in bronchoalveolar fluid extracted from injured lungs92. The time course of HGF induction following lung injury correlates with proliferation of the alveolar epithelial cells82, 93 and lung vascular endothelial cells94. Administration of HGF neutralizing antibodies resulted in reduced DNA synthesis in alveolar epithelial cells after ischemia-reperfusion lung injury in rats95. "
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    ABSTRACT: Pulmonary remodeling is characterized by the permanent and progressive loss of the normal alveolar architecture, especially the loss of alveolar epithelial and endothelial cells, persistent proliferation of activated fibroblasts, or myofibroblasts, and alteration of extracellular matrix. Hepatocyte growth factor (HGF) is a pleiotropic factor, which induces cellular motility, survival, proliferation, and morphogenesis, depending upon the cell type. In the adult, HGF has been demonstrated to play a critical role in tissue repair, including in the lung. Administration of HGF protein or ectopic expression of HGF has been demonstrated in animal models of pulmonary fibrosis to induce normal tissue repair and to prevent fibrotic remodeling. HGF-induced inhibition of fibrotic remodeling may occur via multiple direct and indirect mechanisms including the induction of cell survival and proliferation of pulmonary epithelial and endothelial cells, and the reduction of myofibroblast accumulation.
    Preview · Article · Jan 2011 · Acta Pharmacologica Sinica
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    • "Emphysema is characterized by the disappearance of alveolar septa, and widespread destruction of the pulmonary vascular beds. Since HGF is a morphogen of alveolar cells49) and endothelial cells,88) HGF is expected to attenuate emphysema-related pathological events.106,107) Shigemura et al. reported that HGF levels in lung tissue and plasma from rats suffering from elastase-induced emphysema increased, and then declined to below basal levels.107) "
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    ABSTRACT: It has been more than 25 years since HGF was discovered as a mitogen of hepatocytes. HGF is produced by stromal cells, and stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its receptor, c-Met. In fetal stages, HGF-neutralization, or c-Met gene destruction, leads to hypoplasia of many organs, indicating that HGF signals are essential for organ development. Endogenous HGF is required for self-repair of injured livers, kidneys, lungs and so on. In addition, HGF exerts protective effects on epithelial and non-epithelial organs (including the heart and brain) via anti-apoptotic and anti-inflammatory signals. During organ diseases, plasma HGF levels significantly increased, while anti-HGF antibody infusion accelerated tissue destruction in rodents. Thus, endogenous HGF is required for minimization of diseases, while insufficient production of HGF leads to organ failure. This is the reason why HGF supplementation produces therapeutic outcomes under pathological conditions. Moreover, emerging studies delineated key roles of HGF during tumor metastasis, while HGF-antagonism leads to anti-tumor outcomes. Taken together, HGF-based molecules, including HGF-variants, HGF-fragments and c-Met-binders are available as regenerative or anti-tumor drugs. Molecular analysis of the HGF-c-Met system could provide bridges between basic biology and clinical medicine.
    Preview · Article · Jun 2010 · Proceedings of the Japan Academy Ser B Physical and Biological Sciences
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