Fibrosis is identified as a chronic side effect occurring after radiotherapy treatment for abdominal-pelvic tumors in 5 to 10 % of patient. This pathological healing process is characterized by an excessive accumulation of extracellular matrix deposition synthesized by mesenchymal cells. Endothelial to mesenchymal transition (EndoMT), is a processes during which endothelial cells express mesenchymal markers in response to stress. EndoMT is identified as a new source of mesenchymal cells taking part to fibrosis development in patients suffered from inflammation bowel diseases and in a preclinical model. Then, this study focused on the potential participation of EndoMT in radiation-induced intestinal fibrosis and tried to identify new therapeutics targets.
Interestingly, our results showed for the first time EndoMT in rectal tissue from patient who received radiotherapy. We used an in vivo approach by following the mesenchymal cells having an endothelial origin in a mouse model expressing the GFP under the control of an endothelial promoter, Tie2 (Tie2-GFP). Thereby, our results confirmed the existence of radiation-induced EndoMT in our preclinical model. In vitro characterization showed that radiation-induced a modulation of the endothelial phenotype through a mesenchymal profile, a hallmark of EndoMT.
In a second part, we focused on a potential molecular actor named Hey2. In this context, we generated a transgenic mouse model in which Hey2 gene expression is repress especially in the endothelial compartment and observed a decrease in radiation-induced mucosal damage. Our results highlighted that radiation-induced EndoMT process associated with Hey2 overexpression. Inhibiting Hey2 expression could represent a new therapeutic strategy.