Abstract
Mesenchymal−epithelial transition events are related to embryonic development, tissue construction, and wound healing. Stem cells are involved in all of these processes, at least in part. However, the direct evidence of mesenchymal−epithelial transition associated with stem cells is unclear. To determine whether mesenchymal−epithelial transition occurs in liver development and/or the differentiation process of hepatic stem cells in vitro, we analyzed a variety of murine liver tissues from embryonic day 11.5 to adults and the colonies derived from hepatic stem/progenitor cells isolated with flow cytometry. The results of gene expression, immunohistochemistry and Western blot showed that as liver develops, the expression of epithelial markers such as Cytokeratin18 and E-cadherin increase, while expression of mesenchymal markers such as vimentin and N-cadherin decreased. On the other hand, in freshly isolated hepatic stem cells, the majority of cells (65.0%) co-express epithelial and mesenchymal markers; this proportion is significantly higher than observed in hematopoietic cells, non-hematopoietic cells and non-stem cell fractions. Likewise, in stem cell-derived colonies cultured over time, upregulation of epithelial genes (Cytokeratin-18 and E-cadherin) occurred simultaneously with downregulation of mesenchymal genes (vimentin and Snail1). Furthermore, in the fetal liver, vimentin-positive cells in the non-hematopoietic fraction had distinct proliferative activity and expressed early the hepatic lineage marker alpha-fetoprotein.ConclusionHepatic stem cells co-express mesenchymal and epithelial markers; the mesenchymal−epithelial transition occurred in both liver development and differentiation of hepatic stem/progenitor cells in vitro. Besides as a mesenchymal marker, vimentin is a novel indicator for cell proliferative activity and undifferentiated status in liver cells.
Highlights
Mesenchymal-epithelial transition (MET) events are defined as those in which mesenchymal cells lose their motile, migratory properties and acquire cell polarity and adhesion to epithelia
Mesenchymal2epithelial transition is a spontaneous process involved in mouse liver development
To investigate mesenchymal-epithelial transition in liver development, we analyzed the phenotype of cells and MET molecules in developing and adult mouse livers (Figure 1)
Summary
Mesenchymal-epithelial transition (MET) events are defined as those in which mesenchymal cells lose their motile, migratory properties and acquire cell polarity and adhesion to epithelia. MET and the reverse process, epithelial mesenchymal transition (EMT), both occur in normal tissue, including gastrulating and regenerating tissue, as well as abnormal tissues of fibrotic organs or tumors [1,2]. It is necessary to reveal the relationship between EMT/MET and stem cells. Induced pluripotent stem cells (iPSCs) are derived from mouse embryonic fibroblasts (MEF) by MET at the early stage of reprogramming [4,5,6]. These results suggest the possibility that MET is associated with stem cell activities
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