Abstract
Wilson’s disease (WD) is an inherited metabolic disease arising from ATPase copper transporting beta gene (ATP7B) mutation. Orthotoropic liver transplantation is the only radical treatment of fulminant WD, although appropriate donors are lacking at the onset of emergency. Given the hepatogenic capacity and tissue-integration/reconstruction ability in the liver of stem cells from human exfoliated deciduous teeth (SHED), SHED have been proposed as a source for curing liver diseases. We hypothesized the therapeutic potential of SHED and SHED-converted hepatocyte-like- cells (SHED-Heps) for fulminant WD. SHED and SHED-Heps were transplanted into WD model Atp7b-mutated Long-Evans Cinnamon (LEC) rats received copper overloading to induce a lethal fulminant liver failure. Due to the superior copper tolerance via ATP7B, SHED-Hep transplantation gave more prolonged life-span of fulminant LEC rats than SHED transplantation. The integrated ATP7B-expressing SHED-Heps showed more therapeutic effects on to restoring the hepatic dysfunction and tissue damages in the recipient liver than the integrated naïve SHED without ATP7B expression. Moreover, SHED-Heps could reduce copper-induced oxidative stress via ATP7B- independent stanniocalcin 1 secretion in the fulminant LEC rats, suggesting a possible role for paracrine effect of the integrated SHED-Heps. Taken together, SHED-Heps offer a potential of functional restoring, bridging, and preventive approaches for treating fulminant WD.
Highlights
Wilson’s disease (WD) is an autosomal recessive disorder[1] and caused by a mutation in the human ATPase copper transporting beta gene (ATP7B), which is a critical gene for hepatic copper metabolism[2,3]
These findings suggested that Stem cells from human exfoliated deciduous teeth (SHED) induced under the present hepatogenic condition express, at least in partially, a feature of hepatocyte-like cells
Our in vitro findings indicate that a subpopulation of human post-natal mesenchymal stem cells (MSCs), SHED, can, at least in partially, differentiate into human post-natal MSC-converted hepatocyte-like cells, SHED-Heps, with the sequential stimulation of non-genetic hepatogenic factors, which were evaluated in the previous hepatic induction of human MSCs33
Summary
Wilson’s disease (WD) is an autosomal recessive disorder[1] and caused by a mutation in the human ATPase copper transporting beta gene (ATP7B), which is a critical gene for hepatic copper metabolism[2,3]. Given recent success in allogeneic transplant therapy using primary hepatocytes[11,12,13] and Atp7b-transfected allogenic mesenchymal stem cells (MSCs)[14] in the LEC rats, cell therapy is suggested to be effective in rescuing, delaying, and preventing fulminant WD. Current clinical trials of human MSC- and primary hepatocyte-transplantation provide clinical successes in fulminant hepatic failure[19,20] and metabolic disorders[21,22,23,24,25]. Human MSCs show a superior therapeutic efficacy compared to human MSC-converted hepatocyte-like cells in drug- induced fulminant hepatic failure model mice[26]. No transplant study using MSCs and MSC-converted hepatocyte-like cells in fulminant hepatic failure of congenital hepatic metabolic diseases such as WD has been reported. We transplanted SHED-Heps and SHED into LEC rats with fulminant hepatitis under copper overloading and investigated the life-span and the therapeutic efficacy to the fulminant hepatitis in the copper- overloaded LEC rats
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