Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Am J Pathol. 2018 Sep;188(9):2025-2041. doi: 10.1016/j.ajpath.2018.05.013. Epub 2018 Jun 20.
Intestinal epithelial cell wound healing involves cell migration, proliferation, and differentiation. Although numerous studies have analyzed the migration of absorptive epithelial cells during wound healing, it remains unclear how goblet cells restitute and how MUC2 mucin production affects this process. In this study, we examined the role of high MUC2 production in goblet cell migration during wound healing and demonstrated that during high MUC2 output, goblet cells migrated slower because of impaired production of wound healing factors and endoplasmic reticulum (ER) stress. Two goblet cell lines, HT29-H and HT29-L, that produced high and low MUC2 mucin, respectively, were used. HT29-L healed wounds faster than HT29-H cells by producing significantly higher amounts of fibroblast growth factor (FGF) 1, FGF2, vascular endothelial growth factor-C, and matrix metallopeptidase 1. Predictably, treatment of HT29-H cells with recombinant FGF2 significantly enhanced migration and wound healing. High MUC2 biosynthesis in HT29-H cells induced ER stress and delayed migration that was abrogated by inhibiting ER stress with tauroursodeoxycholic acid and IL-22. FGF2- and IL-22-induced wound repair was dependent on STAT1 and STAT3 signaling. During wound healing after dextran sulfate sodium-induced colitis, restitution of Math1 goblet cells occurred earlier in the proximal colon, followed by the middle and then distal colon, where ulceration was severe. We conclude that high MUC2 output during colitis impairs goblet cell migration and wound healing by reducing production of growth factors critical in wound repair.
肠上皮细胞的伤口愈合涉及细胞迁移、增殖和分化。虽然有许多研究分析了吸收上皮细胞在伤口愈合过程中的迁移，但 goblet 细胞如何恢复以及 MUC2 粘蛋白的产生如何影响这一过程仍不清楚。在这项研究中，我们研究了高 MUC2 产生在 goblet 细胞迁移中的作用，结果表明，在高 MUC2 产生的情况下，由于伤口愈合因子和内质网（ER）应激的产生受损， goblet 细胞迁移速度较慢。我们使用了两种分别产生高和低 MUC2 粘蛋白的 goblet 细胞系，HT29-H 和 HT29-L。HT29-L 通过产生显著更高量的成纤维细胞生长因子（FGF）1、FGF2、血管内皮生长因子-C 和基质金属蛋白酶 1 来更快地愈合伤口。可以预见的是，用重组 FGF2 处理 HT29-H 细胞显著增强了迁移和伤口愈合。HT29-H 细胞中高 MUC2 生物合成诱导 ER 应激并延迟迁移，用牛磺熊脱氧胆酸和 IL-22 抑制 ER 应激可消除这种延迟。FGF2 和 IL-22 诱导的伤口修复依赖于 STAT1 和 STAT3 信号。在葡聚糖硫酸钠诱导的结肠炎后，Math1 goblet 细胞的恢复在近端结肠更早发生，然后是中间和远端结肠，这些部位溃疡严重。我们得出结论，结肠炎期间高 MUC2 输出通过减少对伤口修复至关重要的生长因子的产生，损害 goblet 细胞的迁移和伤口愈合。
