Stem Cell Therapy for Liver Diseases
Date Issued
2016
Date
2016
Author(s)
Huang, Yu-Jen
Abstract
Cell transplantation are expected to replace the whole organ transplantation as the first therapeutic choice for patients with organ failure. Hepatocyte transplantation has been proved with the ability of treating a wide variety of liver disease in both animal experiments and clinical studies. However, the hepatocytes shortage and allograft rejection remained unsolved during the development of hepatocyte transplantation. On the other hand, stem cell therapy has been shown to have the therapeutic potential in many kinds of diseases, and the autograft of stem cell is suggested as the key of organ shortage and allograft rejection. Therefore, the stem cell transplantation is gathering the attention with the potential of being the next therapeutic strategy for liver diseases. For the reason, various cell types have been tried, whether in animal models or in clinical trials, to repair or regenerate the damage tissue. In this dissertation, we allowed hepatocyte-like cell derived from induce pluripotent stem cells (iPSCs) and adipose stem cells (ASCs) generated from omentum adipose tissue as the candidates, and addressed their therapeutic potential in inherited diseases-hemophilia B and acute liver failure (ALF) induced by acetaminophen (APAP), respectively. iPSCs, shared some characteristics with the ESCs, have been demonstrated with the capability of differentiating into different somatic cells. However, whether hepatocytes differentiated from iPSCs is functioning with the therapeutic efficiency of genetic liver disease, the hemophilia B disease (factor IX knockout mice model), has never been proved. Our data showed that iPSCs derived hepatocytes shared many characteristics with hepatocytes, including albumin synthesis, metabolic capacity, glycogen storage, and ureagenesis. In fact, iPSCs-derived hepatocytes transplantation led to increased coagulation factor IX activity, improved thrombus generation, and better hemostasis parameters, moreover, the transferred cells were localized in the liver in recipient HB mice. As a result, hepatocyte-like cells derived from iPSCs is suggested to be a potential cell source for cell-based therapy in the treatment of HB. Another study is about the therapeutic potential of omentum derived adipose stem cells in APAP-induced ALF. We successfully acquired the ASCs from omentum adipose tissue, and proved the antioxidant activity of the candidate. Our data showed that ASCs transplantation significantly improved the survival rate of mice with ALF, and attenuated the severity of APAP-induced liver damage by suppressing cytochrome P450 activity. Following the activity, the cell reduced the accumulation of toxic nitrotyrosine and the upregulation of NF-E2-related factor 2 (Nrf2) expression, and in sequential resulted in the increase of antioxidant activity. Taken together, our results suggested the stem cell therapy is an opportunity to open up entirely new perspectives for treatment of severe liver diseases.
Subjects
Cell transplantation
Organ transplantation
Stem cell therapy
induce pluripotent stem cells
Omentum adipose stem cells
Clotting factor IX
Acetaminophen
Acute liver failure
Type
thesis
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