Improvement of carbon tetrachloride-induced acute hepatic failure by transplantation of induced pluripotent stem cells without reprogramming factor c-Myc.

Abstract

The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl(4))-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl(4)-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl(4)-treated mice. CCl(4)-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases.

• Authors: Hua-Ming Chang, Yi-Wen Liao, Chih-Hung Chiang, Yi-Jen Chen, Ying-Hsiu Lai, Yuh-Lih Chang, Hen-Li Chen, Shaw-Yeu Jeng, Jung-Hung Hsieh, Chi-Hsien Peng, Hsin-Yang Li, Yueh Chien, Szu-Yu Chen, Liang-Kung Chen, Teh-Ia Huo
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 13 Issue 3 Pg. 3598-3617 ( 2012) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 22489170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Myc protein, mouse
• Octamer Transcription Factor-3
• Proto-Oncogene Proteins c-myc
• Reactive Oxygen Species
• SOXB1 Transcription Factors
• Sox2 protein, mouse
• Carbon Tetrachloride

Topics

• Animals
• Antioxidants (metabolism)
• Carbon Tetrachloride (adverse effects)
• Cell Differentiation
• Cell Survival
• Cell- and Tissue-Based Therapy (methods)
• Cells, Cultured
• Cellular Reprogramming
• Chemical and Drug Induced Liver Injury (therapy)
• Disease Models, Animal
• Hepatic Encephalopathy (therapy)
• Hepatocytes (metabolism)
• Induced Pluripotent Stem Cells (transplantation)
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (biosynthesis)
• Liver (pathology)
• Liver Failure, Acute (chemically induced, therapy)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Octamer Transcription Factor-3 (biosynthesis)
• Proto-Oncogene Proteins c-myc (deficiency, genetics)
• Reactive Oxygen Species (metabolism)
• SOXB1 Transcription Factors (biosynthesis)