Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.
Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.
J Hepatol. 2021 Sep;75(3):690-705. doi: 10.1016/j.jhep.2021.04.048. Epub 2021 May 11.
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.
目前，人们对功能性原代人肝细胞的需求尚未得到满足，这些肝细胞将用于支持药物和（生物）医学需求。十年前，人们惊奇地发现，体细胞可以摆脱其明显的生物学锁定状态，重新获得多能性，这为生成替代的人肝细胞开辟了一条全新的途径。从那时起，大量报道体细胞直接转化为诱导性肝细胞（iHeps）的论文如雨后春笋般涌现。通过在体细胞中异位表达内源性肝富集转录因子，可以建立肝细胞命运，从而无需中间（多能性）干细胞状态。也就是说，理解并最终控制产生功能性 iHeps 的过程仍然具有挑战性。在这篇综述中，我们概述了最先进的重编程鸡尾酒和技术，以及它们相应的转化效率。特别关注肝富集转录因子作为肝生成重编程工具的作用，以及小分子作为肝转分化促进剂的作用。最后，我们提出了优化、标准化和丰富 iHeps 体外生产以达到临床标准的建议，并提出了其特征描述的最低标准。
