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 seemingly biological lockdown to acquire once again a pluripotent state, has paved a complete new avenue of possibilities to generate surrogate human hepatocytes. Since then, the number of papers reporting the direct conversion of somatic cells into induced hepatocytes (iHeps) has thrived. Via ectopic expression of native liver-enriched transcription factors in somatic cells a hepatic cell fate is established, thereby bypassing the need for an intermediate (pluripotent) stem cell state. Though, understanding and eventually controlling these processes that give rise to functional iHeps still remain a challenge. In this review we provide a state of the art overview of the actually explored 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 characterization.

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Authors: Matthias Rombaut, Joost Boeckmans, Robim M Rodrigues, Leo A van Grunsven, Tamara Vanhaecke, Joery De Kock