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Generation of liver bipotential organoids with a small-molecule cocktail 
Xin Wang1,† , Chao Ni1,† , Ning Jiang1 , Jinsong Wei1 , Jianqing Liang1 , Bing Zhao1,* , Xinhua Lin1,*
1State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China
These authors contributed equally to this work
*Correspondence to:Bing Zhao , Xinhua Lin ,
J Mol Cell Biol, Volume 12, Issue 8, August 2020, Pages 618-629
Keyword: liver bipotential organoid, small-molecule cocktail, long-term expansion, progenitor cell, hepatocyte differentiation, liver regeneration

Understanding the mechanism of how cholangiocytes (liver ductal cells) are activated upon liver injury and specified to hepatocytes would permit liver regenerative medicine. Here we achieved long-term in vitro expansion of mouse liver organoids by modulating signaling pathways with a combination of three small-molecule compounds. CHIR-99021, blebbistatin, and forskolin together maintained the liver organoids in bipotential stage with both cholangiocyte- and hepatocyte-specific gene expression profiles and enhanced capacity for further hepatocyte differentiation. By employing a chemical approach, we demonstrated that Wnt/β-catenin, NMII–Rac, and PKA–ERK are core signaling pathways essential and sufficient for mouse liver progenitor expansion. Moreover, the advanced small-molecule culture of bipotential organoids facilitates the ex vivo investigation of liver cell fate determination and the application of organoids in liver regenerative medicine.