title: Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells.
abstract: Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14-deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14-deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14-deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14-deficient livers. We demonstrate that MMP-14-mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Otani
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan; Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: skakinuma.gast@tmd.ac.jp.
authors.forename: Sei
authors.initials: S
authors.lastname: Kakinuma
authors.affiliation: Institute of Innovative Science and Technology, Tokai University, Isehara, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Goto
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Miyoshi
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Fukiko
authors.initials: F
authors.lastname: Kawai-Kitahata
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Nitta
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakata
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itsui
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Seishin
authors.initials: S
authors.lastname: Azuma
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan; Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Asahina
authors.affiliation: Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Koshikawa
authors.affiliation: Medical School, Kanazawa University, Kanazawa, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: mamoru.gast@tmd.ac.jp.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000166:cytology* / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*
chemical_list: C507096:Mmp14 protein, mouse; D053511:Matrix Metalloproteinase 14
keywords: Biliary differentiation; Cholangiocytic cyst; MMP-14–deficient mouse; Mitogen-activated protein kinase