Service de Recherche en Radiobiologie et en Médecine Régénérative (SERAMED), Laboratoire de Radiobiologie des Expositions Médicales (LRMED), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, F-92260 Paris, France.
Int J Mol Sci. 2021 Feb 11;22(4):1790. doi: 10.3390/ijms22041790.
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.
纤维化是西方国家主要的死亡原因。越来越多的纤维化患者需要创新的治疗方法。尽管间充质干细胞 (MSC) 治疗对纤维化有已证实的有益效果，但在结直肠纤维化中，其抗纤维化作用的证据很少。已经在 Sprague-Dawley 大鼠体内研究了 MSC 减少辐射引起的结直肠纤维化的能力。在局部辐射暴露后，在纤维化开始前给大鼠注射 MSC。MSC 通过控制细胞外基质 (ECM) 周转来下调纤维化。为了更好地理解这些机制，我们使用了存在人 MSC 的辐照共培养结直肠纤维化的体外模型。结肠中的促纤维化细胞主要是肠成纤维细胞和平滑肌细胞。肠成纤维细胞和平滑肌细胞在未辐照 MSC 的存在下被辐照和共培养。MSC 介导促纤维化基因表达和蛋白分泌的减少。MSC 中肝细胞生长因子 (HGF) 和肿瘤坏死因子刺激基因 6 (TSG-6) 的沉默证实了这两个基因的互补作用。HGF 和 TSG-6 通过减少平滑肌细胞和肌成纤维细胞的激活来限制纤维化的进展。为了在体内确定 HGF 和 TSG-6 在 MSC 抗纤维化作用中的贡献，用沉默 HGF 或 TSG-6 的 MSC 处理大鼠。移植的 MSC 中 HGF 和 TSG-6 的沉默导致 ECM 在结肠中的沉积显著增加。这些结果强调了 MSC 影响与纤维化相关疾病的病理生理学的潜力，这是创新治疗的一个具有挑战性的领域。
