Non-viral FoxM1 gene delivery to hepatocytes enhances liver repopulation.
Hepatocyte transplantation as a substitute strategy of orthotopic liver transplantation is being studied for treating end-stage liver diseases. Several technical hurdles must be overcome in order to achieve the therapeutic liver repopulation, such as the problem of insufficient expansion of the transplanted hepatocytes in recipient livers. In this study, we analyzed the application of FoxM1, a cell-cycle regulator, to enhance the proliferation capacity of hepatocytes. The non-viral sleeping beauty (SB) transposon vector carrying FoxM1 gene was constructed for delivering FoxM1 into the hepatocytes. The proliferation capacities of hepatocytes with FoxM1 expression were examined both in vivo and in vitro. Results indicated that the hepatocytes with FoxM1 expression had a higher proliferation rate than wild-type (WT) hepatocytes in vitro. In comparison with WT hepatocytes, the hepatocytes with FoxM1 expression had an enhanced level of liver repopulation in the recipient livers at both sub-acute injury (fumaryl acetoacetate hydrolase (Fah)(-/-) mice model) and acute injury (2/3 partial hepatectomy mice model). Importantly, there was no increased risk of tumorigenicity with FoxM1 expression in recipients even after serial transplantation. In conclusion, expression of FoxM1 in hepatocytes enhanced the capacity of liver repopulation without inducing tumorigenesis. FoxM1 gene delivered by non-viral SB vector into hepatocytes may be a viable approach to promote therapeutic repopulation after hepatocyte transplantation.
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Xiang
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Liu
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Wang
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Li
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Chen
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Yao
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Yu
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Lu
The Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, China.
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Borjigin
1] Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA [2] Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
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Chen
1] School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China [2] Shenzhen Center for ADR Monitoring, Shenzhen, China.
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Zhong
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Wangensteen
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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He
1] The Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, China [2] Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA [3] Hepatoscience Incorporation, Palo Alto, CA, USA.
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Wang
1] Department of Cell Biology, Second Military Medical University, Shanghai, China [2] Center for Stem Cell and Medicine, The Graduate School, Second Military Medical University, Shanghai, China.
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Hu
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013997:Time Factors; D014162:Transfection; D019895:Transposases / Q000235:genetics
D004268:DNA-Binding Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C499308:Rag2 protein, mouse; D019895:Transposases; D006867:Hydrolases; C020156:fumarylacetoacetase