Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Am J Physiol Gastrointest Liver Physiol. 2024 Jul 1;327(1):G70-G79. doi: 10.1152/ajpgi.00074.2024. Epub 2024 May 7.
Although impaired regeneration is important in many gastrointestinal diseases including ulcerative colitis (UC), the dynamics of mucosal regeneration in humans are poorly investigated. We have developed a model to study these processes in vivo in humans. Epithelial restitution (ER) and extracellular matrix (ECM) regulation after an experimental injury of the sigmoid colonic mucosa was assessed by repeated high-resolution endoscopic imaging, histological assessment, RNA sequencing, deconvolution analysis, and 16S rDNA sequencing of the injury niche microbiome of 19 patients with UC in remission and 20 control subjects. Human ER had a 48-h lag before induction of regenerative epithelial cells [wound-associated epithelial (WAE) and transit amplifying (TA) cells] along with the increase of fibroblast-derived stem cell growth factor gremlin 1 mRNA (). However, UC deconvolution data showed rapid induction of inflammatory fibroblasts and upregulation of major structural ECM collagen mRNAs along with tissue inhibitor of metalloproteinase 1 (), suggesting increased profibrotic ECM deposition. No change was seen in transforming growth factor β () mRNA, whereas the profibrotic cytokines interleukin 13 () and were upregulated in UC, suggesting that human postinjury responses could be TGFβ-independent. In conclusion, we found distinct regulatory layers of regeneration in the normal human colon and a potential targetable profibrotic dysregulation in UC that could lead to long-term end-organ failure, i.e., intestinal damage. The study reveals the regulatory dynamics of epithelial regeneration and extracellular matrix remodeling after experimental injury of the human colon in vivo and shows that human intestinal regeneration is different from data obtained from animals. A lag phase in epithelial restitution is associated with induction of stromal cell-derived epithelial growth factors. Postinjury regeneration is transforming growth factor β-independent, and we find a profibrotic response in patients with ulcerative colitis despite being in remission.
虽然在包括溃疡性结肠炎（UC）在内的许多胃肠道疾病中，受损的再生能力很重要，但人类黏膜再生的动力学仍未得到充分研究。我们开发了一种模型，以在体内研究人类的这些过程。通过对 19 例缓解期 UC 患者和 20 例对照患者的乙状结肠黏膜进行重复高分辨率内镜成像、组织学评估、RNA 测序、损伤龛微生态 16S rDNA 测序、脱卷积分析，评估上皮修复（ER）和细胞外基质（ECM）在实验性损伤后的调节。UC 患者中，在诱导再生上皮细胞（WAE 和 TA 细胞）之前，人类 ER 有 48 小时的潜伏期，同时成纤维细胞衍生的干细胞生长因子 Gremlin-1mRNA 增加（）。然而，UC 脱卷积数据显示，炎症性成纤维细胞迅速诱导和主要结构 ECM 胶原 mRNA 上调，同时组织金属蛋白酶抑制剂 1（），提示 ECM 沉积增加。转化生长因子-β（）mRNA 没有变化，而 UC 中促纤维化细胞因子白细胞介素 13（）和 上调，提示人类损伤后反应可能与 TGFβ 无关。总之，我们发现正常人类结肠有不同的再生调节层，UC 中有潜在的可靶向的促纤维化失调，可能导致长期终末器官衰竭，即肠道损伤。该研究揭示了人类结肠在体内实验性损伤后上皮再生和细胞外基质重塑的调节动力学，并表明人类肠道再生与从动物获得的数据不同。上皮修复的潜伏期与基质细胞衍生的上皮生长因子的诱导有关。损伤后再生与转化生长因子-β无关，我们发现即使在缓解期，UC 患者也存在促纤维化反应。
