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Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation.

Li B, Zheng YW, Sano Y, Taniguchi H - PLoS ONE (2011)

Bottom Line: However, the direct evidence of mesenchymal-epithelial transition associated with stem cells is unclear.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

ABSTRACT

Unlabelled: 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.

Conclusion: Hepatic 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.

Show MeSH
A Schematic model for MET.MET is involved in stem cell inactivation, cell polarization and differentiation. This process is associated with a reduction of vimentin and accumulation of CK8/18 in stem cells. Furthermore, the variation of vimentin in stem cells is an indicator of cell proliferative activity. Conversely, it is suggested that EMT causes cells into active and de-differentiated state and acquire stem cell-like characteristics. M: mesenchymal state; E: epithelial state; Vim: vimentin.
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pone-0017092-g007: A Schematic model for MET.MET is involved in stem cell inactivation, cell polarization and differentiation. This process is associated with a reduction of vimentin and accumulation of CK8/18 in stem cells. Furthermore, the variation of vimentin in stem cells is an indicator of cell proliferative activity. Conversely, it is suggested that EMT causes cells into active and de-differentiated state and acquire stem cell-like characteristics. M: mesenchymal state; E: epithelial state; Vim: vimentin.

Mentions: Although the link between stem cells and vimentin-positive cells in fetal liver has not been completely elucidated, we suggest that vimentin is a critical indicator for activated cells experiencing MET. Accordingly, because of the elastic state of stem cells, our results provide a hint that MET in stem cells indicates rearrangement of cytoskeleton as well. During the process of inactivating mesenchymal cells or the developing fetal liver, the number of vimentin-positive cells decreased (Figures 6 and 7).


Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation.

Li B, Zheng YW, Sano Y, Taniguchi H - PLoS ONE (2011)

A Schematic model for MET.MET is involved in stem cell inactivation, cell polarization and differentiation. This process is associated with a reduction of vimentin and accumulation of CK8/18 in stem cells. Furthermore, the variation of vimentin in stem cells is an indicator of cell proliferative activity. Conversely, it is suggested that EMT causes cells into active and de-differentiated state and acquire stem cell-like characteristics. M: mesenchymal state; E: epithelial state; Vim: vimentin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037942&req=5

pone-0017092-g007: A Schematic model for MET.MET is involved in stem cell inactivation, cell polarization and differentiation. This process is associated with a reduction of vimentin and accumulation of CK8/18 in stem cells. Furthermore, the variation of vimentin in stem cells is an indicator of cell proliferative activity. Conversely, it is suggested that EMT causes cells into active and de-differentiated state and acquire stem cell-like characteristics. M: mesenchymal state; E: epithelial state; Vim: vimentin.
Mentions: Although the link between stem cells and vimentin-positive cells in fetal liver has not been completely elucidated, we suggest that vimentin is a critical indicator for activated cells experiencing MET. Accordingly, because of the elastic state of stem cells, our results provide a hint that MET in stem cells indicates rearrangement of cytoskeleton as well. During the process of inactivating mesenchymal cells or the developing fetal liver, the number of vimentin-positive cells decreased (Figures 6 and 7).

Bottom Line: However, the direct evidence of mesenchymal-epithelial transition associated with stem cells is unclear.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

ABSTRACT

Unlabelled: 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.

Conclusion: Hepatic 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.

Show MeSH