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Published on: August 24, 2013
Epimorphin, a morphogenic protein, induces proteases in rodent hepatocytes through NF-kappaB
Kouichi Miura1, Ryutaro Yoshino, Yohei Hirai
1Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
Background/Aims:
Epimorphin, expressed by hepatic stellate cells in the liver, directs normal morphogenesis in various organs. The aim of this study was to clarify the mechanism by which epimorphin functions as a morphogen in vitro.
Methods:
Male Balb/c mice and Sprague-Dawley rats were used. First, we explored the relationship between epimorphin expression and distribution of protease-positive cells in carbon tetrachloride-induced acute liver injury. We then examined protease levels in cultured hepatocytes and signal transduction of epimorphin. Finally, we determined the requirement for proteases and NF-kappaB in spheroid formation induced by epimorphin.
Results:
Epimorphin expression was enhanced in injured areas during late recovery phase, in which protease-positive hepatocytes were localized adjacent to epimorphin-expressing cells. In vitro, epimorphin induced matrix metalloproteinase (MMP) 9, MMP 3 and urokinase type plasminogen activator (uPA) in hepatocytes. NF-kappaB mediated these protease expressions in hepatocytes. These proteases were required for epimorphin-induced and Matrigel induced spheroid. An epimorphin-neutralizing antibody also blocked spheroid formation on Matrigel, which contained epimorphin. In addition, NF-kappaB activation was also required for spheroid formation.
Conclusion:
Epimorphin elicits hepatocyte spheroids by inducing proteases in rodent hepatocytes through NF-kappaB.
