Ratih Yuniartha1,2, Takayoshi Yamaza3, Soichiro Sonoda4, Koichiro Yoshimaru1, Toshiharu Matsuura1, Haruyoshi Yamaza5, Yoshinao Oda6, Shouichi Ohga7, Tomoaki Taguchi1,8. 1. Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. 2. Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. 3. Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. yamazata@dent.kyushu-u.ac.jp. 4. Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 5. Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, Fukuoka, Japan. 6. Department of Anatomic Pathology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. 7. Department of Pediatrics, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. 8. Fukuoka College of Health Sciences, Fukuoka, Japan.
Abstract
BACKGROUND: Stem cells from human exfoliated deciduous teeth (SHED) have been reported to show the in vivo and in vitro hepatic differentiation, SHED-Heps; however, the cholangiogenic potency of SHED-Heps remains unclear. Here, we hypothesized that SHED-Heps contribute to the regeneration of intrahepatic bile duct system in chronic fibrotic liver. METHODS: SHED were induced into SHED-Heps under cytokine stimulation. SHED-Heps were intrasplenically transplanted into chronically CCl4-treated liver fibrosis model mice, followed by the analysis of donor integration and hepatobiliary metabolism in vivo. Immunohistochemical assay was examined for the regeneration of intrahepatic bile duct system in the recipient liver. Furthermore, SHED-Heps were induced under the stimulation of tumor necrosis factor alpha (TNFA). RESULTS: The intrasplenic transplantation of SHED-Heps into CCl4-treated mice showed that donor SHED-Heps behaved as human hepatocyte paraffin 1- and human albumin-expressing hepatocyte-like cells in situ and ameliorated CCl4-induced liver fibrosis. Of interest, the integrated SHED-Heps not only expressed biliary canaliculi ATP-binding cassette transporters including ABCB1, ABCB11, and ABCC2, but also recruited human keratin 19- (KRT19-) and KRT17-positive cells, which are considered donor-derived cholangiocytes, regenerating the intrahepatic bile duct system in the recipient liver. Furthermore, the stimulation of TNFA induced SHED-Heps into KRT7- and SRY-box 9-positive cells. CONCLUSIONS: Collectively, our findings demonstrate that infused SHED-Heps showed cholangiogenic ability under the stimulation of TNFA in CCl4-damaged livers, resulting in the regeneration of biliary canaliculi and interlobular bile ducts in chronic fibrotic liver. Thus, the present findings suggest that SHED-Heps may be a novel source for the treatment of cholangiopathy.
BACKGROUND: Stem cells from human exfoliated deciduous teeth (SHED) have been reported to show the in vivo and in vitro hepatic differentiation, SHED-Heps; however, the cholangiogenic potency of SHED-Heps remains unclear. Here, we hypothesized that SHED-Heps contribute to the regeneration of intrahepatic bile duct system in chronic fibrotic liver. METHODS: SHED were induced into SHED-Heps under cytokine stimulation. SHED-Heps were intrasplenically transplanted into chronically CCl4-treated liver fibrosis model mice, followed by the analysis of donor integration and hepatobiliary metabolism in vivo. Immunohistochemical assay was examined for the regeneration of intrahepatic bile duct system in the recipient liver. Furthermore, SHED-Heps were induced under the stimulation of tumor necrosis factor alpha (TNFA). RESULTS: The intrasplenic transplantation of SHED-Heps into CCl4-treated mice showed that donor SHED-Heps behaved as human hepatocyte paraffin 1- and humanalbumin-expressing hepatocyte-like cells in situ and ameliorated CCl4-induced liver fibrosis. Of interest, the integrated SHED-Heps not only expressed biliary canaliculi ATP-binding cassette transporters including ABCB1, ABCB11, and ABCC2, but also recruited humankeratin 19- (KRT19-) and KRT17-positive cells, which are considered donor-derived cholangiocytes, regenerating the intrahepatic bile duct system in the recipient liver. Furthermore, the stimulation of TNFA induced SHED-Heps into KRT7- and SRY-box 9-positive cells. CONCLUSIONS: Collectively, our findings demonstrate that infused SHED-Heps showed cholangiogenic ability under the stimulation of TNFA in CCl4-damaged livers, resulting in the regeneration of biliary canaliculi and interlobular bile ducts in chronic fibrotic liver. Thus, the present findings suggest that SHED-Heps may be a novel source for the treatment of cholangiopathy.
Entities:
Keywords:
Cholangiocyte; Chronic liver fibrosis; Human deciduous pulp stem cell-converted hepatocyte-like cells; Intrahepatic bile duct regeneration; Tumor necrosis factor alpha
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