title: HST-1/FGF-4 plays a critical role in crypt cell survival and facilitates epithelial cell restitution and proliferation.
abstract: The fibroblast growth factor-4 (HST-1/FGF-4) is a heparin-binding growth factor that influences on epithelial and many other cells through interaction with FGF receptors. It has been demonstrated that the HST-1/FGF-4 gene protects mice from lethal irradiation by preventing bone marrow damage and intestinal tract damage. However, the radioprotective mechanism is unknown. In this study, we have investigated the expression of Hst-1/Fgf-4 in mouse small intestine after irradiation, and determined the role of HST-1/FGF-4 in mouse intestinal crypt cell survival and epithelial cell proliferation and restitution. We found the induction of endogenous Hst-1/Fgf-4 expression in intestine when mice are exposed to 9.0 Gy irradiation. Laser-captured microdissection (LCM) coupled with RT-PCR analysis revealed that expression of Hst-1/Fgf-4 was found in epithelial cell of the villi and crypt cells. Pretreatment of HST-1/FGF-4 caused an increase in the number of surviving crypt cells, and clearly suppresses the radiation-induced apoptosis of the crypt cells. Moreover, exogenous HST-1/FGF-4 enhances epithelial cell restitution and proliferation in an in vitro model. These data suggest that HST-1/FGF-4 is induced by irradiation injury, and that HST-1/FGF-4 will find a therapeutic role in the prevention of intestinal cell toxicity following intensive chemotherapy and radiation therapy protocols, and in allogenic cell transplantation.
authors.affiliation: Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1 Tsukiji, 5-chome, Chuoku, Tokyo 104-0045, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Sasaki
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hirai
authors.forename: Hanako
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanooka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Teruaki
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Terada
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D004847:Epithelial Cells / Q000378:metabolism* / Q000528:radiation effects; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000528:radiation effects; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats
chemical_list: C496445:FGF4 protein, human; C496446:Fgf4 protein, mouse; C496447:Fgf4 protein, rat; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D005346:Fibroblast Growth Factors