Cell fate conversion: Direct induction of hepatocyte‐like cells from fibroblasts

Abstract

One of the essential features of stem cells is their cellular plasticity to differentiate into daughter cells with defined functions. Recently, induction of pluripotent stem cells from somatic cells by defined transcription factors led to the focus on cellular plasticity of terminally differentiated cells. This approach is adopted by other studies to demonstrate the cell fate conversion between different lineages of terminally differentiated cells. We and others showed that induced hepatocyte-like (iHep) cells are directly converted from mouse fibroblasts by overexpression of liver-enriched transcription factors. iHep cells as well as pluripotent stem cell- or mesenchymal stem cell-derived hepatocyte-like cells provide potential cell sources for disease modeling, transplantation, and tissue engineering independent of donor organs. Here, we review the latest advances in generating hepatocyte-like cells and summarize general criteria for evaluating these cells. In addition, we propose a possible role of the p19(Arf) /p53 pathway in cell fate maintenance, which apparently limits the formation of induced pluripotent stem (iPS) cells and iHep cells.

Baf60b-mediated ATM-p53 activation blocks cell identity conversion by sensing chromatin opening

“…Our previous study showed that p19Arf inactivation facilitates induced hepatic (iHep) cell formation 12,14 . Because p19Arf is a key regulator of the p53 pathway 15,16 , we asked whether p53 acted as a roadblock to hepatic conversion.…”

“…However, the molecular basis of the “barrier” remains largely elusive. Specifically, given the importance to maintain cell identity and the plasticity of epigenetic modifications, it is interesting to ask whether there is an essential cellular mechanism beyond the epigenetic “barrier” that senses cell identity change and consequently blocks the process 12,14 . We approached this question by characterizing Foxa3, Hnf1α and Gata4 (3TF)-induced hepatic conversion in mouse fibroblasts 12 .…”

Generation of non-viral, transgene-free hepatocyte like cells with piggyBac transposon

“…iHeps are expected to be an alternative to hepatocytes in many situations27, such as a serving as a cell source for transplantation in severe liver dysfunction, in vitro disease modeling, pharmacokinetic analyses, and differentiation or regeneration modeling in the hepatic lineage. In the initial reports on mouse iHeps, Suzuki et al 12.…”

In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity

“…For decades, expandable HHs have been a bottleneck for their applications for research purposes and clinical therapies (Bhatia et al, 2014;Michalopoulos, 2014;Mitaka, 1998;Runge et al, 2000). Human hepatocyte-like cells (HLCs) have been generated from human pluripotent stem cells by in vitro differentiation or from human somatic cells by direct transdifferentiation (Ji et al, 2013). This method was able to generate large numbers of functional HLCs capable of rescuing liver failure in mice after transplantation.…”