Stages based molecular mechanisms for generating cholangiocytes from liver stem/progenitor cells

Abstract

Except for the most organized mature hepatocytes, liver stem/progenitor cells (LSPCs) can differentiate into many other types of cells in the liver including cholangiocytes. In addition, LSPCs are demonstrated to be able to give birth to other kinds of extra-hepatic cell types such as insulin-producing cells. Even more, under some bad conditions, these LSPCs could generate liver cancer stem like cells (LCSCs) through malignant transformation. In this review, we mainly concentrate on the molecular mechanisms for controlling cell fates of LSPCs, especially differentiation of cholangiocytes, insulin-producing cells and LCSCs. First of all, to certificate the cell fates of LSPCs, the following three features need to be taken into account to perform accurate phenotyping: (1) morphological properties; (2) specific markers; and (3) functional assessment including in vivo transplantation. Secondly, to promote LSPCs differentiation, systematical attention should be paid to inductive materials (such as growth factors and chemical stimulators), progressive materials including intracellular and extracellular signaling pathways, and implementary materials (such as liver enriched transcriptive factors). Accordingly, some recommendations were proposed to standardize, optimize, and enrich the effective production of cholangiocyte-like cells out of LSPCs. At the end, the potential regulating mechanisms for generation of cholangiocytes by LSPCs were carefully analyzed. The differentiation of LSPCs is a gradually progressing process, which consists of three main steps: initiation, progression and accomplishment. It’s the unbalanced distribution of affecting materials in each step decides the cell fates of LSPCs.

Keywords: Liver stem/progenitor cells, Cholangiocytes, Biliary differentiation, Unbalanced distribution of materials, Cell therapy

Core tip: After liver stem/progenitor cells (LSPCs) are isolated by different groups from both fetal and adult livers, it is urgent to decide the cell fates of LSPCs. Especially, it is found that the core issue for LSPCs application lies in their accurate differentiation. Because there are lots of literatures concentrating on self-renewal and hepatic differentiation of LSPCs, in this review, we mainly summarize the molecular mechanisms for controlling other cell fates of LSPCs, especially differentiation into cholangiocytes. For biliary differentiation, we propose that it is a gradually progressing process consisting of three main steps: initiation, progression and accomplishment.