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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



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ID: 717286.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
MicroRNA-199a-5p inhibition enhances the liver repopulation ability of human embryonic stem cell-derived hepatic cells
Authors:Möbus, S.; Yang, D.; Yuan, Q.; Ludtke, T. H.; Balakrishnan, A.; Sgodda, M.; Rani, B.; Kispert, A.; Arauzo-Bravo, M. J.; Vogel, A.; Manns, M. P.; Ott, M.; Cantz, T.; Sharma, A. D.
Date of Publication (YYYY-MM-DD):2015-08-15
Title of Journal:Journal of Hepatology
Volume:62
Start Page:101
End Page:110
Review Status:Internal review
Audience:Not Specified
Abstract / Description:BACKGROUND & AIMS: Current hepatic differentiation protocols for human embryonic stem cells (ESCs) require substantial improvements. MicroRNAs (miRNAs) have been reported to regulate hepatocyte cell fate during liver development, but their utility to improve hepatocyte differentiation from ESCs remains to be investigated. Therefore, our aim was to identify and to analyze hepatogenic miRNAs for their potential to improve hepatocyte differentiation from ESCs. METHODS: By miRNA profiling and by miRNA screening, we identified miR-199a-5p among several potential hepatogenic miRNAs. Transplantation studies of miR-199a-5p-inhibited hepatocyte-like cells (HLCs) into the liver of immunodeficient fumarylacetoacetate knockout (Fah-/-/Rag2-/-/Il2rg-/-) mice were performed to assess the in vivo liver repopulation potential. For target determination, western blot and luciferase reporter assay were carried out. RESULTS: MiRNA profiling revealed 20 conserved candidate hepatogenic miRNAs. By miRNA screening, only miR-199a-5p inhibition in HLCs was found to be able to enhance the in vitro hepatic differentiation from mouse as well as human ESCs. MiR-199a-5p inhibition in human ESCs-derived HLCs enhanced the engraftment and repopulation capacity in the liver of Fah-/-/Rag2-/-/Il2rg-/- mice. Furthermore, we identified SMARCA4 and MST1 as novel targets of miR-199a-5p that may contribute to the improved hepatocyte generation and in vivo liver repopulation. CONCLUSIONS: Our findings demonstrate that miR-199a-5p inhibition in ES-derived HLCs leads to improved hepatocyte differentiation and upon transplantation, are able to engraft and repopulate the liver of Fah-/-/Rag2-/-/Il2rg-/- mice. Thus, our findings suggest that miRNA modulation may serve as promising approach to generate more mature HLCs from stem cell sources for the treatment of liver diseases.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; WINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7-9, 30625 Hannover, Germany. Institute for Molecular Biology Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Computational Biology and Bioinformatics Group, Max Planck Institute for Molecular Biomedicine, Rontgenstr. 20, 48149 Munster, Germany. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Computational Biology and Bioinformatics Group, Max Planck Institute for Molecular Biomedicine, Rontgenstr. 20, 48149 Munster, Germany. Electronic address: cantz.tobias@mh-hannover.de. Junior Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: sharma.amar@mh-hannover.de. %[2014/08/19
Identifiers:ISSN:1600-0641 (Electronic) 0168-8278 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/25135862 [ID No:2]
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