Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 East Zhongshan Road, Nanjing, PR China.
Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, PR China.
J Crohns Colitis. 2023 Aug 21;17(8):1291-1308. doi: 10.1093/ecco-jcc/jjad042.
Mesenteric adipose tissue hypertrophy is a hallmark of Crohn's disease [CD], and creeping fat [CF] is unique to CD. Adipose-derived stem cells [ASCs] from inflammatory tissue exhibited altered biological functions. The role of ASCs isolated from CF in intestinal fibrosis and the potential mechanism remain unclear.
ASCs were isolated from CF [CF-ASCs] and disease-unaffected mesenteric adipose tissue [Ctrl-ASCs] of patients with CD. A series of in vitro and in vivo experiments were conducted to study the effects of exosomes from CF-ASCs [CF-Exos] on intestinal fibrosis and fibroblast activation. A micro-RNA microarray analysis was performed. Western blot, luciferase assay and immunofluorescence were performed to further detect the underlying mechanisms.
The results indicated that CF-Exos promoted intestinal fibrosis by activating fibroblasts in a dose-dependent manner. They continuously promoted progression of intestinal fibrosis even after dextran sulphate sodium withdrawal. Further analysis showed that exosomal miR-103a-3p was enriched in CF-Exos and participated in exosome-mediated fibroblast activation. TGFBR3 was identified as a target gene of miR-103a-3p. Mechanistically, CF-ASCs released exosomal miR-103a-3p and promoted fibroblast activation by targeting TGFBR3 and promoting Smad2/3 phosphorylation. We also found that the expression of miR-103a-3p in diseased intestine was positively associated with the degree of CF and fibrosis score.
Our findings show that exosomal miR-103a-3p from CF-ASCs promotes intestinal fibrosis by activating fibroblasts via TGFBR3 targeting, suggesting that CF-ASCs are potential therapeutic targets for intestinal fibrosis in CD.
肠系膜脂肪组织肥大是克罗恩病[CD]的标志，而爬行脂肪[CF]是 CD 所特有的。来自炎症组织的脂肪源性干细胞[ASCs]表现出改变的生物学功能。源自 CF 的 ASC 在肠道纤维化中的作用及其潜在机制尚不清楚。
从 CD 患者的 CF[CF-ASCs]和未受疾病影响的肠系膜脂肪组织[Ctrl-ASCs]中分离 ASC。进行了一系列的体外和体内实验，以研究 CF-ASC 来源的外泌体[CF-Exos]对肠道纤维化和成纤维细胞激活的影响。进行了 micro-RNA 微阵列分析。进行 Western blot、荧光素酶测定和免疫荧光进一步检测潜在机制。
结果表明，CF-Exos 以剂量依赖的方式激活成纤维细胞，从而促进肠道纤维化。即使在葡聚糖硫酸钠撤出后，它们也能持续促进肠道纤维化的进展。进一步分析表明，外泌体 miR-103a-3p 在 CF-Exos 中富集，并参与外泌体介导的成纤维细胞激活。TGFBR3 被鉴定为 miR-103a-3p 的靶基因。从机制上讲，CF-ASCs 通过释放外泌体 miR-103a-3p 并通过靶向 TGFBR3 促进 Smad2/3 磷酸化来促进成纤维细胞激活。我们还发现，疾病肠道中 miR-103a-3p 的表达与 CF 的程度和纤维化评分呈正相关。
我们的研究结果表明，源自 CF-ASCs 的外泌体 miR-103a-3p 通过靶向 TGFBR3 激活成纤维细胞来促进肠道纤维化，这表明 CF-ASCs 是 CD 中肠道纤维化的潜在治疗靶点。
