Journal
CELL REPORTS
Volume 15, Issue 4, Pages 814-829Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.03.071
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [2011-0013885, 2011-0019490]
- Bio & Medical Technology Development Program of the NRF
- Korean Government, MSIP [2015M3A9C7030091]
- Next-Generation BioGreen21 program, Rural Development Administration, Republic of Korea [PJ011311]
- National Research Foundation of Korea [2011-0019490, 2011-0013885] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Recent studies have shown that defined factors could lead to the direct conversion of fibroblasts into induced hepatocyte-like cells (iHeps). However, reported conversion efficiencies are very low, and the underlying mechanism of the direct hepatic reprogramming is largely unknown. Here, we report that direct conversion into iHeps is a stepwise transition involving the erasure of somatic memory, mesenchymal-to-epithelial transition, and induction of hepatic cell fate in a sequential manner. Through screening for additional factors that could potentially enhance the conversion kinetics, we have found that c-Myc and Klf4 (CK) dramatically accelerate conversion kinetics, resulting in remarkably improved iHep generation. Furthermore, we identified small molecules that could lead to the robust generation of iHeps without CK. Finally, we show that Hnf1 alpha supported by small molecules is sufficient to efficiently induce direct hepatic reprogramming. This approach might help to fully elucidate the direct conversion process and also facilitate the translation of iHep into the clinic.
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