Colonic epithelial wound healing by anal transitional cells

项目摘要 粘膜愈合是所有炎症性肠病（IBD）治疗的主要目标。没有当前 经批准的治疗直接促进肠上皮的伤口愈合，肠上皮形成单细胞屏障 并调节免疫反应。细胞和分子机制， 治疗过程还有待确定。肠腺维持上皮细胞的正常更新， 在基底干细胞和终末分化的管腔细胞的垂直谱系层次内的细胞。创面 愈合时，这种谱系层次被暂停，上皮细胞可以经历去分化以介导再分化。 上皮化在最近的工作中，我们已经确定了一个替代来源的伤口愈合的远端结肠， 小鼠在急性和慢性结肠炎模型中，肛门过渡区（ATZ）的皮肤样细胞群， 毗邻尖锐的鳞状柱状肛门直肠交界处，迁移到结肠并形成永久性杂交 上皮结构称为结肠鳞状新上皮（SNEC）。SNEC代表的最终产品 通过ATZ的细胞的伤口愈合。ATZ是一个解剖学上的小区域，由独特的 具有混合结肠/表皮表型并且能够创伤-愈合的上皮干细胞群体。 愈合可塑性此外，这些干细胞对结肠炎的损害具有部分抵抗力。研究这些 细胞可以突出IBD背景下结肠上皮再生的新途径。但 人类ATZ的无数组织类型中的谱系多样性和关系尚不清楚， 此外，ATZ干细胞是否可以提供持久的肠道功能，保护肠道功能， 从潜在的致癌后遗症，或修复整个结肠溃疡。在拟议的工作中，我们将测试 ATZ衍生的干细胞是否可以是介导结肠上皮伤口愈合的合适试剂， 确定有助于其增殖潜力的关键途径。该项目的具体目标是：1） 定义人ATZ中的再生细胞群，2）定义内源性结肠炎的长期结果， 通过ATZ细胞的伤口愈合，和3）鉴定伤口愈合中功能性ATZ可塑性的机制。一 更深入地研究这种非规范形式的机制，含义和潜在的翻译， 结肠伤口愈合可以揭示新的治疗靶点，以指导IBD的粘膜愈合。

PROJECT SUMMARY Mucosal healing is the primary goal of all therapies for inflammatory bowel disease (IBD). No currently approved therapy directly promotes wound healing of the bowel epithelium, which forms a single-cell barrier between the host and lumen and regulates the immune response. The cellular and molecular mechanisms that define the healing process remain to be defined. The intestinal crypt maintains the normal turnover of epithelial cells within a vertical lineage hierarchy of basal stem and terminally differentiated luminal cells. During wound healing, this lineage hierarchy is suspended, and epithelial cells can undergo dedifferentiation to mediate re- epithelialization. In recent work, we have identified an alternate source of wound healing in the distal colon of mice. In acute and chronic models of colitis, a skin-like cell population at the anal transition zone (ATZ), bordering the sharp squamocolumnar anorectal junction, migrates into the colon and forms a permanent hybrid epithelial structure called squamous neo-epithelium of colon (SNEC). SNEC represents the end-product of wound healing by cells of the ATZ. The ATZ is an anatomically small region that is composed of a unique population of epithelial stem cells that have a mixed colonic/epidermal phenotype and are capable of wound- healing plasticity. Moreover, these stem cells are partially resistant to the damage of colitis. The study of these cells could highlight new pathways for colonic epithelial regeneration in the context of IBD. However, the lineage diversity and relationships within the myriad tissue types of the human ATZ are not known, and furthermore it remains to be defined whether ATZ stem cells might provide enduring intestinal function, protect from potential oncogenic sequela, or repair ulcers throughout the colon. In the proposed work, we will test whether ATZ-derived stem cells could be suitable reagents to mediate colonic epithelial wound healing and identify key pathways that contribute to their proliferative potential. The Specific Aims of the project are: 1) to define regenerative cell populations in the human ATZ, 2) to define long-term outcomes of endogenous colonic wound healing by ATZ cells, and 3) to identify mechanisms of functional ATZ plasticity in wound healing. A deeper investigation of the mechanisms, implications, and potential translation of this noncanonical form of colonic wound healing could reveal new therapeutic targets to direct mucosal healing in IBD.