Abstract
Fibrosis is a leading cause of death in occidental states. The increasing number of patients with fibrosis requires innovative approaches. Despite the proven beneficial effects of mesenchymal stem cell (MSC) therapy on fibrosis, there is little evidence of their anti-fibrotic effects in colorectal fibrosis. The ability of MSCs to reduce radiation-induced colorectal fibrosis has been studied in vivo in Sprague–Dawley rats. After local radiation exposure, rats were injected with MSCs before an initiation of fibrosis. MSCs mediated a downregulation of fibrogenesis by a control of extra cellular matrix (ECM) turnover. For a better understanding of the mechanisms, we used an in vitro model of irradiated cocultured colorectal fibrosis in the presence of human MSCs. Pro-fibrotic cells in the colon are mainly intestinal fibroblasts and smooth muscle cells. Intestinal fibroblasts and smooth muscle cells were irradiated and cocultured in the presence of unirradiated MSCs. MSCs mediated a decrease in profibrotic gene expression and proteins secretion. Silencing hepatocyte growth factor (HGF) and tumor necrosis factor-stimulated gene 6 (TSG-6) in MSCs confirmed the complementary effects of these two genes. HGF and TSG-6 limited the progression of fibrosis by reducing activation of the smooth muscle cells and myofibroblast. To settle in vivo the contribution of HGF and TSG-6 in MSC-antifibrotic effects, rats were treated with MSCs silenced for HGF or TSG-6. HGF and TSG-6 silencing in transplanted MSCs resulted in a significant increase in ECM deposition in colon. These results emphasize the potential of MSCs to influence the pathophysiology of fibrosis-related diseases, which represent a challenging area for innovative treatments.
Highlights
Fibrosis appears in most tissues further to an injury
Based on the need to better manage colorectal fibrosis, we aimed to investigate mediators and mechanisms that are involved in protection of mesenchymal stem cell (MSC) against pelvic radiotherapyinduced fibrosis
Sprague–Dawley rats were exposed to a single dose of 29 Gy, which was delivered to a 2 × 3 cm colorectal (Figure 1A), in order to obtain severe radiation-induced epithelial alterations histologically
Summary
Fibrosis appears in most tissues further to an injury. These pathologies greatly impact the quality of life of the patients, and their prevalence is high, in developed countries. Similar to IBDs, radiation can induce colorectal damage such as severe mucosal damage, chronic inflammation and activation of pro-fibrotic genes. Chronic insults, such as those induced by persisting inflammation, prevent proper tissue regeneration and continuously activate repair pathways. These injuries lead to differentiation of resident and
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