Hepatocyte Growth Factor Region Specifically Stimulates Gastrointestinal Epithelial Growth in Primary Culture

Fukamachi, Hiroshi; Ichinose, Masakazu; Tsukada, Sachiyuki; Kakei, Nobuyuki; Suzuki, Takahiko; Miki, Kazumasa; Kurokawa, Kiyoshi; Masui, Tohru

doi:10.1006/bbrc.1994.2827

Cited by 56 publications

(18 citation statements)

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“…The coincident timing of HGF up-regulation and crypt cell hyperproliferation strongly suggests an involvement of HGF in the stimulation of crypt cell proliferation as a prelude to the intestinal mucosal regeneration. This finding is consistent with previous in vitro studies reporting HGF to be a potent mitogen for intestinal epithelial cells (Dignass et al, 1994;Fukamachi et al, 1994). Our study is also consistent with in vivo studies demonstrating that exogenous HGF increased intestinal mass and function after massive small bowel resection (Kato et al, 1998).…”

Section: Discussionsupporting

confidence: 93%

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

et al. 2000

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Summary Chemotherapy or radiotherapy often cause mucosal damage in the gut (gut mucositis) in cancer patients. As a step to investigate mechanisms underlying subsequent intestinal repair, we have examined the expression profiles of hepatocyte growth factor (HGF) and its receptor c-met, two molecules previously implicated in tissue repair, in comparison to the histopathological and proliferative changes in a rat model of methotrexate-induced small intestinal mucositis. Histological analysis of the intestinal specimens revealed crypt loss and villus atrophy with damage maximal on day 5 after methotrexate injection, and normalization of mucosal structure commencing on day 6. Crypt cell proliferation was decreased dramatically on day 3, normalized on day 4 and up-regulated on days 5 and 6. HGF and c-met protein/mRNA expression was up-regulated between days 4 and 7, with the mRNA co-localizing to the crypt and lower villus epithelium. Therefore, following methotrexate injection, a decrease in crypt cell proliferation preceded histological damage, and conversely, crypt cell hyperproliferation preceded mucosal regeneration. Up-regulation of HGF and c-met coincided with crypt hyperproliferation and mucosal recovery, suggesting a role for HGF in intestinal repair following acute injury. The crypt epithelial localization of HGF and c-met implies an autocrine or paracrine mechanism of HGF action. All these procedures were approved by the Animal Ethics Committee of the Women's and Children's Hospital, Adelaide, Australia. Histopathological analysis of intestinal damage and repairTransverse sections (4 µm in thickness) of paraffin-embedded proximal jejunal specimens were stained with haematoxylin and eosin (H&E) and examined with a light microscope. A semi-quantitative histological assessment of intestinal damage was utilized to obtain an overall score of damage severity. A total score for the sample was derived from the sum of scores for 11 histopathological criteria as we have previously described (Howarth et al, 1996), including villus fusion and stunting (atrophy), disruption of brush border and surface enterocytes, disappearance of goblet cells, reduction in numbers of mitotic figures, crypt loss/architectural disruption, disruption or distortion of crypt cells, crypt abscess formation, infiltration of polymorphonuclear cells and lymphocytes and dilatation of lymphatics and capillaries. For each criterion, a score was given to represent a mild (score 1), moderate (2), severe (3), or no (0) changes. Quantitative histological analyses were also conducted to measure the changes in crypt depth and villus height in the jejunal specimens over the time course. Microscopic images were acquired and analysed. For each animal, the height and depth of ten villi and crypts respectively were measured at three tissue levels, each separated by 100 µm, and means of the 30 measurements were calculated for each animal. Although histological damage prevented accurate measurements of villus and crypt lengths in some regions, in the jejunal ...

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Section: Discussionsupporting

confidence: 93%

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

et al. 2000

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“…These results suggest that HGF/SF-Met signaling participates in digestive system morphogenesis. Moreover, previous studies demonstrated that HGF/SF can stimulate both esophageal and gastrointestinal epithelial growth in primary cultures (Fukamachi et al, 1994;Takahashi et al, 1995). HGF/SF was also shown to enhance both intestinal mucosal repair and function in vivo (Kato et al, 1997a(Kato et al, , 1997bNishimura et al, 1998).…”

Section: Discussionmentioning

confidence: 96%

Ulcerative Proctitis, Rectal Prolapse, and Intestinal Pseudo-Obstruction in Transgenic Mice Overexpressing Hepatocyte Growth Factor/Scatter Factor

Takayama

Takagi

LaRochelle

et al. 2001

Laboratory Investigation

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SUMMARY:Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro;however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (IBD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent. (Lab Invest 2001, 81:297-305).H epatocyte growth factor/scatter factor (HGF/ SF) was first identified as a highly potent hepatocyte mitogen (Gohda et al, 1988;Nakamura et al, 1989) but is now known as a multifunctional cytokine based on its ability to stimulate proliferation, movement, and/or morphogenesis of a broad spectrum of cultured epithelial cells expressing the tyrosine kinase receptor encoded by the c-met proto-oncogene (Gherardi and Stoker, 1991;Montesano et al, 1991;Rosen et al, 1994;Rubin et al, 1991;Vande Woude, 1992;Zarnegar and Michalopoulos, 1995). HGF/SF is produced in cells of mesenchymal origin, whereas c-met is expressed in adult and embryonic epithelium, implicating HGF/SF-Met signal transduction pathways as important in the epithelial-mesenchymal interaction that occurs during embryogenesis, tissue organization, and organogenesis. Gene targeting studies have shown that HGF/SF-Met signaling is required for the normal development of liver, skeletal muscle, and placenta Schmidt et al, 1995;Uehara et al, 1995).In the fetal digestive tract, c-met transcripts were found in the epithelia of the intestinal anlagen and the villi, whereas the distribution of HGF/SF RNA showed dynamic changes during mouse development by in situ hybridization (Sonnenberg et al, 1993). Immunohistochemical analysis of temporal expression revealed that both HGF/SF and c-Met could be detected between 7 and 8 weeks of gestation in human fetal digestive tissues (Kermorgant et al, 1997). These results suggest that HGF/SF-Met signaling participates in digestive system morphogenesis. Moreover, previous studies demonstrated that HGF/SF can stimulate both esophageal ...

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“…It is well known that diffusible growth factors mediate tis- sue interactions in several systems of organogenesis (Fukamachi et al, 1994;Nogawa and Ito, 1995;Post et al, 1996;Vukicevic et al, 1996;Koike and Yasugi, 1999). Hepatic mesenchyme, lung mesenchyme and stomach mesenchyme can induce hepatocyte differentiation in hepatic endodermal cells at the second step of the hepatic induction, but somitic mesenchyme and metanephric mesenchyme are impotent (Le Douarin, 1975;Fukuda-Taira, 1981;Koike and Shiojiri, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…During development of several organs, including the salivary gland, lung, kidney, and stomach, diffusible growth factors from the mesenchyme stimulate growth, morphogenesis and cell differentiation of their epithelial cells (Fukamachi et al, 1994;Nogawa and Ito, 1995;Post et al, 1996;Vukicevic et al, 1996;Koike and Yasugi, 1999). Direct cell-cell contacts and extracellular matrices have also been shown to play crucial roles in these organogenesis systems (Schuger et al, 1996;Kadoya et al, 1997;Müller et al, 1997;Yang et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Both Humoral Mesenchymal Factors and the Close Association between the Hepatic Endoderm and Mesenchyme can be Involved in Liver Formation of Mouse Embryos

Abe

Shiojiri

2000

ZOO SCI

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Hepatocyte Growth Factor Region Specifically Stimulates Gastrointestinal Epithelial Growth in Primary Culture

Cited by 56 publications

References 0 publications

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

Ulcerative Proctitis, Rectal Prolapse, and Intestinal Pseudo-Obstruction in Transgenic Mice Overexpressing Hepatocyte Growth Factor/Scatter Factor

Both Humoral Mesenchymal Factors and the Close Association between the Hepatic Endoderm and Mesenchyme can be Involved in Liver Formation of Mouse Embryos

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