Journal
STEM CELL REPORTS
Volume 11, Issue 1, Pages 22-31Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2018.05.001
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Funding
- National Key R&D Program of China [2017YFA0102800, 2017YFA0103700, 2016YFA0500102, 2016YFC1304905]
- Chinese Academy of Sciences [XDA16030402, ZDRW-ZS-2017-1, KFZD-SW-213]
- National Natural Science Foundation of China [31670829, 81630086, 81427805, 91529305]
- National Youth 1000 Talents Program
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Hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) offer a promising cell resource for disease modeling and transplantation. However, differentiated HLCs exhibit an immature phenotype and comprise a heterogeneous population. Thus, a better understanding of HLC differentiation will improve the likelihood of future application. Here, by taking advantage of CRISPR-Cas9-based genome-wide screening technology and a high-throughput hPSC screening platform with a reporter readout, we identified several potential genetic regulators of HLC differentiation. By using a chemical screening approach within our platform, we also identified compounds that can further promote HLC differentiation and preserve the characteristics of in vitro cultured primary hepatocytes. Remarkably, both screenings identified histone deacetylase 3 (HDAC3) as a key regulator in hepatic differentiation. Mechanistically, HDAC3 formed a complex with liver transcriptional factors, e.g., HNF4, and co-regulated the transcriptional program during hepatic differentiation. This study highlights a broadly useful approach for studying and optimizing hPSC differentiation.
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