Direct reprogramming of somatic cells into induced hepatocytes: Cracking the Enigma code

There is an unmet need for functional primary human hepatocytes to support the pharmaceutical and (bio)medical demand. The unique discovery, a decade ago, that somatic cells can be drawn out of their apparent biological lockdown to reacquire a pluripotent state has revealed a completely new avenue o...

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Bibliographic Details
Published in:Journal of hepatology 2021-09, Vol.75 (3), p.690-705
Main Authors: Rombaut, Matthias, Boeckmans, Joost, Rodrigues, Robim M., van Grunsven, Leo A., Vanhaecke, Tamara, De Kock, Joery
Format: Article
Language:English
Subjects:
Adult Stem Cells - metabolism
Adult Stem Cells - physiology
bench-to-bedside
Cell fate
Cell Transdifferentiation - physiology
Direct hepatic reprogramming
Ectopic expression
Hepatocytes
Hepatocytes - metabolism
Hepatocytes - physiology
Humans
induced hepatocytes
Liver
liver-enriched transcription factor
Pluripotency
Somatic cells
Stem cells
Transcription factors
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Summary:There is an unmet need for functional primary human hepatocytes to support the pharmaceutical and (bio)medical demand. The unique discovery, a decade ago, that somatic cells can be drawn out of their apparent biological lockdown to reacquire a pluripotent state has revealed a completely new avenue of possibilities for generating surrogate human hepatocytes. Since then, the number of papers reporting the direct conversion of somatic cells into induced hepatocytes (iHeps) has burgeoned. A hepatic cell fate can be established via the ectopic expression of native liver-enriched transcription factors in somatic cells, thereby bypassing the need for an intermediate (pluripotent) stem cell state. That said, understanding and eventually controlling the processes that give rise to functional iHeps remains challenging. In this review, we provide an overview of the state-of-the-art reprogramming cocktails and techniques, as well as their corresponding conversion efficiencies. Special attention is paid to the role of liver-enriched transcription factors as hepatogenic reprogramming tools and small molecules as facilitators of hepatic transdifferentiation. To conclude, we formulate recommendations to optimise, standardise and enrich the in vitro production of iHeps to reach clinical standards, and propose minimal criteria for their characterisation.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2021.04.048