ABSTRACT
BACKGROUND: Until now, there is no effective anti-fibrotic therapy available for liver cirrhosis. Stem cell therapies have been studied for the treatment of hepatic fibrosis. However, the use of embryonic stem cells or induced pluripotent stem cells (iPSC) has limitations such as ethical concern or malignancy potential. Induced hepatocyte-like cells (iHEPs) generated by direct reprogramming technology may overcome these limitations. METHODS: In this study, we generated iHEPs by direct reprogramming from mouse embryonic fibroblast (MEF) either using specific transcription factors such as c-Myc and Klf-4 (type A), or adding small molecules to HNF1α (type B). RESULTS: We investigated the effect of iHEPs on acute liver injury and chronic hepatic fibrosis animal models induced by CCl4 intra-peritoneal injection in BALB/C nude mice. In acute liver injury model, serum AST/ALT levels peaked at 24 h after CCl4 injection. Intra-splenic transplantation of iHEPs significantly attenuated CCl4-induced acute liver injury. GFP-labeled iHEPs (type A) migrated to the liver after intra-splenic transplantation that was confirmed by Western blotting and immunofluorescence staining. We found that GFP and albumin were co-localized in migrated iHEPs in the liver suggesting migrated iHEPs were functional. In chronic hepatic fibrosis mice experiment, transplantation of either type A or type B iHEPs significantly attenuated liver fibrosis induced by CCl4 injection for 10 weeks. CONCLUSIONS: Our study suggests that iHEPs may be used as a novel therapeutic strategy for the treatment of hepatic fibrosis.
Subject(s)
Cell Differentiation/genetics , Hepatocytes/transplantation , Induced Pluripotent Stem Cells/transplantation , Liver Cirrhosis/therapy , Animals , Carbon Tetrachloride/toxicity , Cellular Reprogramming/genetics , Disease Models, Animal , Hepatocytes/cytology , Humans , Liver/growth & development , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/pathology , Liver Function Tests , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , MiceABSTRACT
Somatic cells could be directly converted into induced neural stem cells (iNSCs) by ectopic expression of defined transcription factors. However, the underlying mechanism of direct lineage transition into iNSCs is largely unknown. In this study, we examined the effect of genetic background on the direct conversion process into an iNSC state. The iNSCs from two different mouse strains exhibited the distinct efficiency of lineage conversion as well as clonal expansion. Furthermore, the expression levels of endogenous NSC markers, silencing of transgenes, and in vitro differentiation potential were also different between iNSC lines from different strains. Therefore, our data suggest that the genetic background of starting cells influences the conversion efficiency as well as reprogramming status of directly converted iNSCs.
