Abstract
Bone marrow-derived mesenchymal stem cells (MSC) have the ability to differentiate into a variety of cell types and are a potential source for epithelial tissue repair. Several studies have demonstrated their ability to repopulate the gastrointestinal tract (GIT) in bone marrow transplanted patients or in animal models of gastrointestinal carcinogenesis where they were the source of epithelial cancers. However, mechanism of MSC epithelial differentiation still remains unclear and controversial with trans-differentiation or fusion events being evoked. This study aimed to investigate the ability of MSC to acquire epithelial characteristics in the particular context of the gastrointestinal epithelium and to evaluate the role of cell fusion in this process. In vitro coculture experiments were performed with three gastrointestinal epithelial cell lines and MSC originating from two patients. After an 8 day coculture, MSC expressed epithelial markers. Use of a semi-permeable insert did not reproduce this effect, suggesting importance of cell contacts. Tagged cells coculture or FISH on gender-mismatched cells revealed clearly that epithelial differentiation resulted from cellular fusion events, while expression of mesenchymal markers on fused cells decreased over time. In vivo cell xenograft in immunodeficient mice confirmed fusion of MSC with gastrointestinal epithelial cells and self-renewal abilities of these fused cells. In conclusion, our results indicate that fusion could be the predominant mechanism by which human MSC may acquire epithelial characteristics when in close contact with epithelial cells from gastrointestinal origin . These results could contribute to a better understanding of the cellular and molecular mechanisms allowing MSC engraftment into the GIT epithelium.
Highlights
Epithelial homeostasis, corresponding to a balance between epithelial cell loss and epithelial cell production, has to be maintained, in the gastrointestinal tract (GIT) where the epithelium needs to be renewed extremely rapidly to ensure its function
In order to better understand the role of mesenchymal stem cells (MSC) in GIT epithelium physiopathology, this study aimed to evaluate the mechanisms by which human bone marrow-derived MSC cultured with epithelial cells may acquire epithelial characteristics in vitro
We demonstrated for the first time that MSC can acquire epithelial characteristics through a fusion mechanism with gastric and intestinal epithelial cells
Summary
Epithelial homeostasis, corresponding to a balance between epithelial cell loss and epithelial cell production, has to be maintained, in the gastrointestinal tract (GIT) where the epithelium needs to be renewed extremely rapidly to ensure its function. Cells originating from extra-gastrointestinal sites and from the bone marrow may take part in the repopulation of epithelial mucosa. Studies on gendermismatched human bone marrow transplants showed that donorderived cells can be retrieved in the epithelium of the gastrointestinal tract (GIT) [2,3,4,5,6]. The role of BMDC in epithelium repair was confirmed in mouse GIT as they can repopulate it in correlation with the level of damage after local irradiation or gastritis induced by chronic infection with Helicobacter felis [7,8,9,10]
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