Highly efficient conversion of mouse fibroblasts into functional hepatic cells under chemical induction

Author:

Zhong Zhi12,Du Jiangchuan2,Zhu Xiangjie23,Guan Lingting2,Hu Yanyu2,Zhang Peilin2,Wang Hongyang12ORCID

Affiliation:

1. Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China

2. National Center for Liver Cancer, Naval Medical University , Shanghai 201805 , China

3. Institute of Metabolism & Integrative Biology, Fudan University , Shanghai 200438 , China

Abstract

Abstract Previous studies have shown that hepatocyte-like cells can be generated from fibroblasts using either lineage-specific transcription factors or chemical induction methods. However, these methods have their own deficiencies that restrict the therapeutic applications of such induced hepatocytes. In this study, we present a transgene-free, highly efficient chemical-induced direct reprogramming approach to generate hepatocyte-like cells from mouse embryonic fibroblasts (MEFs). Using a small molecule cocktail (SMC) as an inducer, MEFs can be directly reprogrammed into hepatocyte-like cells, bypassing pluripotent and immature hepatoblast intermediate stages. These chemical-induced hepatocyte-like cells (ciHeps) closely resemble mature primary hepatocytes in terms of morphology, biological behavior, gene expression patterns, marker expression levels, and hepatic functions. Furthermore, transplanted ciHeps can integrate into the liver, promote liver regeneration, and improve survival rates in mice with acute liver damage. ciHeps can also ameliorate liver fibrosis caused by chronic injuries and enhance liver function. Notably, ciHeps exhibit no tumorigenic potential either in vitro or in vivo. Mechanistically, SMC-induced mesenchymal-to-epithelial transition and suppression of SNAI1 contribute to the fate conversion of fibroblasts into ciHeps. These results indicate that this transgene-free, chemical-induced direct reprogramming technique has the potential to serve as a valuable means of producing alternative hepatocytes for both research and therapeutic purposes. Additionally, this method also sheds light on the direct reprogramming of other cell types under chemical induction.

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Genetics,Molecular Biology,General Medicine

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