Department of Radiation Medicine, Faculty of Naval Medicine, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, P.R. China.
School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325000, P.R. China.
Cell Commun Signal. 2024 Oct 29;22(1):524. doi: 10.1186/s12964-024-01902-5.
Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis.
肠干细胞（ISCs）负责肠道内稳态，对于受损肠道的再生非常重要。我们建立了一个电离辐射（IR）诱导的肠道损伤模型，观察到 Gelsolin KO 小鼠的辐射敏感性增加。Gelsolin 的缺失加剧了肠道损伤，并减少了致命 IR 后的 ISC 数量。肠道类器官实验表明，Gelsolin 缺失抑制了 IR 后 ISC 的功能。值得注意的是，RNA 测序和 RT-PCR 结果表明，IL-17 信号通路在 Gelsolin KO 小鼠中下调，Th17 细胞分化受到抑制。此外，重组 IL-17A 改善了 IR 诱导的肠道损伤并促进了 ISC 的再生。为了研究 Gelsolin 在 Th17 细胞分化中的作用，我们使用流式细胞术发现 Gelsolin 通过 p-STAT3/RORγt 轴靶向 Th17 细胞功能。通过建立共培养系统，我们证明 Th17 细胞通过 Gelsolin 缺陷类器官中的自我更新和出芽能力促进了其自身的更新和出芽能力。最后，我们发现 Gelsolin 可预防 DSS 诱导的结肠炎，并且这种保护作用不仅限于 IR 诱导的肠道损伤模型。基于这些结果，我们证明了 Gelsolin 通过 p-STAT3/RORγt 轴维持 Th17 细胞功能来维持 ISC 的再生。
