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Wnt7b and Wnt10a, beta‐catenin independent signaling regulates cholangiocyte proliferation and function during cholestasis
Author(s) -
Kosar Karis,
NejakBowen Kari
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.804.8
Subject(s) - cholangiocyte , wnt signaling pathway , cholestasis , biology , autocrine signalling , cancer research , medicine , paracrine signalling , endocrinology , cell growth , liver injury , hepatocyte , microbiology and biotechnology , signal transduction , cell culture , receptor , in vitro , biochemistry , genetics
Cells found in biliary ducts, are believed to be bipotential cells that are capable of differentiating into both cholangiocytes and hepatocytes, leading researchers to consider them as a sort of stem cells for both the liver and biliary duct. Wnt/beta‐catenin signaling has been implicated as an important factor in hepatoblast atypical ductular reaction and in the liver stem cells of rats and in a variety of liver pathologies, including atypical ductular proliferation during hepatobiliary injury. We have previously shown that liver‐specific b‐catenin knockout (KO) mice exhibited a markedly decreased ductular response after 2 weeks of 0.1% 3,5‐diethoxycarbonyl‐1,4‐dihydro‐collidine (DDC) diet. More recently, we also identified upregulation of specific Wnt proteins in the cholangiocytes during cholestatic liver injury and that mice lacking Wnt secretion from hepatocytes and cholangiocytes (Alb‐cre Wls KO) showed fewer proliferating cholangiocytes and high mortality in response to DDC diet. Therefore, we hypothesize Wnt induces proliferation of cholangiocytes, which may alleviate some of the complications caused by cholangiopathies. Two Wnts of interest for us are Wnt7B and Wnt10A, which we have shown, through in vitro studies, promote proliferation of cholangiocytes in an autocrine manner. These Wnts are specific for cholestasis, as wild‐type (WT) mice show normal expression of Wnt7B and Wnt10A after choline deficient, ethionine‐supplemented diet, which induces hepatocyte injury and ductal hyperplasia unrelated to cholestasis. Proliferation and cell viability were unimpaired in a small cholangiocyte (sm‐cc) cell line after b‐catenin suppression in vitro under normal growth conditions. To confirm these findings, sm‐cc cells were transfected with either Wnt7B or Wnt10A, in combination with either control or b‐catenin siRNA. The absence of b‐catenin did not inhibit the Wnt 7B‐ and 10A‐induced increase in cholangiocyte proliferation. Media from sm‐cc cells transfected with Wnt7B or Wnt10A was also analyzed for cytokine production. Compared to control cells, Wnt7B and Wnt10A induced a significant increase in the expression of cytokines and growth factors such as IL‐1A, IL‐17A, and VEGF, while expression of anti‐inflammatory IL‐2 decreases in the transfected cells. Thus, b‐catenin independent Wnt signaling promotes ductular reaction during cholestasis and may also alter the phenotypic response of proliferating cholangiocytes. Support or Funding Information National Institute of Biomedical Imaging and Bioengineering of the National Institute of Health under Award Number T32EB0010216 UPP Academic Foundation Award 1R01DK103775