Different approaches for transformation of mesenchymal stem cells into hepatocyte-like cells

Abstract

Due to the prominent role of the liver in the body and detoxification, its functionality can be affected in an irreversible manner by diseases. This phenomenon renders the liver to stop working, leading to morbidity and mortality. Therefore, liver transplantation is the only way to tackle this issue.In order to compensate for the lack of adequate healthy liver tissue for transplantation, therapeutic approaches such as hepatocyte transplantation have been proposed as an alternative. Recognizing the fact that mesenchymal stem cells are adult stem cells with the capacity to differentiate into several cell types, different methods have been invented to produce hepatocyte-like cells from mesenchymal stem cells. They can be divided into three main categories, such as addition of cytokines and growth factors, genetic modifications, and adjustment of microenvironment as well as physical parameters.In this review, we attempted to introduce diverse efficient methods for differentiating mesenchymal stem cells and their capability for transformation into hepatocyte-like cells.

Keywords: Hepatocyte-like cells; Mesenchymal stem cells; Transformation.

Fig. 1

MSC differentiation capacities toward verity of cell lines

Fig. 2

The structure of the human umbilical cord with a three-dimensional exploded diagram. The diagram is made by direct tracing the outlines of various features in the histological section, then shifting them along the tilted longitudinal axis. Scale bar = 5 mm [15]

Fig. 3

Molecular pathways in embryogenesis of the liver. Production of the liver parenchymal cells starts from the anterior part of the primary liver bud. FGF from cardiac mesoderm and BMP, which is mediated by SMAD4, interfere in hepatic induction through RAS/MAP kinase pathway and BMP signaling. GATA4 regulates expression of the secreted BMP4, which is highly expressed in the STM mesenchymal cells at the 8-somite stage. At early somite stages WNT signaling acts around 7–11 somites to repress the expression of Hhex. At around 21 somites, the matrix surrounding the basal surface of the epithelium is degraded, and E-cadherin expression is downregulated in the hepatic cells by the action of MMPs. GATA4 and/or GATA6 cause hepatoblast development by transactivating the Hhex promoter. Around 25 somites, Onecut-1 and Onecut-2 are redundantly essential for hepatoblast migration. Prox1 also promotes hepatoblast proliferation and migration from the primary liver bud. Tbx3 normally promotes a hepatocyte fate and represses a cholangiocyte fate through the expression of Hnf4a and c/EBPa. FGF fibroblast growth factor, HNF hepatocyte nuclear factor, BMP bone morphogenetic protein, Fox A Fork-head box protein A, Hhex hematopoietically expressed homeobox, STM septum transversum, MMPs matrix metalloproteinases, c/EBPa CCAAT-enhancer-binding proteins, Tbx3 T-Box 3, Prox1 prospero-related homeobox transcription factor

Fig. 4

In vitro hepatic differentiation pattern. Hepatocytes can be differentiated from ES cells in vitro by mimicking the developmental processes of liver formation. Stepwise differentiation (ES cells → DE → hepatoblasts → immature hepatocytes → mature hepatocytes) adopted from liver developmental processes was applied to produce in vitro HLCs. EGF epidermal growth factor, EGFR epidermal growth factor receptor, ERK1/2 extracellular-signal-regulated kinase 1/2, FGF fibroblast growth factor, HGF hepatocyte growth factor, ITS insulin-transferrin-selenium, MAPK mitogen-activated protein kinase, OSM oncostatin M, PI3K phosphoinositide 3-kinase, NTA nicotinamide, ActA Activin A, BMP bone morphogenetic protein