Review Exploring the cell signalling in hepatocyte differentiation Rebecca Vasconcellos a,b , Érika C. Alvarenga a , Ricardo C. Parreira a,b , Swiany S. Lima a,b , Rodrigo R. Resende a,b, ⁎ a Departamento de Bioquímica e Imunologia, Instituto de Ciência Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil b Instituto Nanocell, Rua Santo Antônio, 420, 35500-041 Divinópolis, MG, Brazil abstract article info Article history: Received 1 July 2016 Received in revised form 18 August 2016 Accepted 18 August 2016 Available online 21 August 2016 The liver is the second largest organ in the human body and is responsible for several functions that directly con- tribute to homeostasis. Hepatocytes are the main parenchymal liver cells that regulate multiple biochemical and metabolic functions and the synthesis of substances important to the body. Mesenchymal stem cells (MSCs) are a group of stem cells derived from the mesoderm, which can be obtained from various tissues. Under certain con- ditions, MSCs can differentiate into several cell types, including hepatocytes. Post-transcriptional regulations of liver development signalling and hepatocyte differentiation have been demonstrated. At the post-transcriptional level, microRNAs have emerged as precursors for determining cell fate during differentiation. MicroRNAs (miRNAs) are small non-coding RNAs involved in the post-transcriptional regulation of gene expression. They can determine the stem cell fate by repressing the translation of target mRNAs. In this review, we outline signal- ling pathways involved in stem cell differentiation to hepatocytes and its interplay with liver development. He- patic differentiation models in two-dimensional and three-dimensional cultures used to analyse signalling mechanisms will be described. We also highlight the possible miRNAs involved in this process and the transdifferentiation signalling mechanisms present in hepatocytes. © 2016 Elsevier Inc. All rights reserved. Keywords: miRNA Stem cells differentiation Hepatocytes Liver development Cell signalling Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773 2. Differentiation in liver development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774 2.1. In vitro hepatic cell differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1775 2.2. In vivo hepatic cell differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1775 3. Intersection of pathways between in vitro and in vivo differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1776 4. Liver differentiation signalling pathways orchestrated by miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1778 4.1. Liver cell types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1778 4.2. Tissue organization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1779 4.3. Liver zonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1780 5. Cross-talk of the extracellular matrix and miRNA in liver cell differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1780 5.1. Influence of extracellular matrix in miRNA regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1782 5.2. Cellular transdifferentiation into induced-hepatocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1783 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1784 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1784 1. Introduction In recent years, stem cells have generated great interest owing to their potential therapeutic uses. Under the influence of environmental factors, including extracellular matrix components, the factors secreted by cells or cell-cell interactions can promote the proliferation, migra- tion, and differentiation into multiple cell types that compose the human body and/or replace the damaged cells from adult tissues [1]. Cell differentiation implies a sequence of orchestrated events that coordinate the conversion of stem cells and precursors to a particular specialised cell type and involves the loss of stem cell characteristics as well as the acquisition of specialised functions and specific markers [2]. At the post-transcriptional level, microRNAs have emerged as pre- cursors in the control of proliferation and cell fate determination during Cellular Signalling 28 (2016) 1773–1788 ⁎ Corresponding author at: Cell Signaling and Nanobiotechnology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Av Antônio Carlos, 6627, Block N4 112, Belo Horizonte, MG 31270-901, Brazil. E-mail addresses: rrresende@institutonanocell.org.br, rrresende@hotmail.com (R.R. Resende). http://dx.doi.org/10.1016/j.cellsig.2016.08.011 0898-6568/© 2016 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Cellular Signalling journal homepage: www.elsevier.com/locate/cellsig