Paradigms of Wound Healing and Fibrosis in the Eye

眼睛伤口愈合和纤维化的范例

• 批准号: 8328686
• 负责人: A. Sue Menko
• 金额: $ 39.41万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328686
• 关键词: Adult; Antibodies; Antigens; Applications Grants; Cataract Extraction; Cell physiology; Cells; Cellular biology; Characteristics; Chick Embryo; Cornea; Cytokine Signaling; DNA biosynthesis; Debridement; Developmental Process; Disease; Embryo; Enzyme Induction; Epiblast; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Eye; Fibrosis; Germ Layers; Healed; Hematopoietic; Injury; Investigation; Knowledge; Link; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Movement; Myofibroblast; Occupations; Paper; Phenotype; Play; Polyploidy; Population; Population Sizes; Process; Property; Proteins; Rattus; Recruitment Activity; Reporting; Role; Signal Pathway; Signal Transduction; Site; Source; Stem cells; Surface Antigens; Time; Tissues; Vimentin; Wound Healing; capsule; cell injury; cell type; corneal epithelium; corneal scar; gene repression; healing; injury and repair; lens; novel; precursor cell; progenitor; repaired; response; response to injury; tissue regeneration; transcription factor; transdifferentiation; wound

Currently the identity of precursors of the mesenchymal cells involved in wound healing and fibrosis are under debate. We propose a novel paradigm in which these cells descend from a unique subpopulation of repair progenitor cells that coexist normally with the cells of epithelial tissues. We have shown the presence of these repair cells in the lens and cornea. In the lens these repair progenitor cells rapidly respond to injury by expanding their population size through a mechanism independent of DNA replication, but likely related to their unusual characteristic of polyploidy. The signals that mediate the expansion of the progenitor cells, their reprogramming to a repair phenotype and the rapid targeting of the repair cells to the wound edge are unknown. While the repair cells function at the site of injury as regulators of the healing process, they also have the potential to trandifferentiate to a myofibroblast phenotype, the cell type linked to fibrosis. This proposal examines this novel wound healing paradigm in both lens and cornea injury models with the following questions: 1) Are the repair progenitor cells novel descendents of a hematopoietic lineage?; 2) What is the mechanism by which repair cell progenitors rapidly expand in response to injury of their host epithelium?; 3) How are mesenchymal progenitor cells signaled to migrate to the wound edge?; 4) What is the fate of the mesenchymal cells after they complete their job of regulating wound repair?; and 5) What are the conditions that induce the repair cells to acquire the mature myofibroblast phenotype associated with disease states such as fibrosis? These studies are expected to have a major impact in the fields of cell biology and wound healing by shifting the study of the regulators of wound healing and source of myofibroblasts to this novel progenitor population.

目前，参与伤口愈合和纤维化的间充质细胞前体的鉴定 辩论。我们提出了一种新的范式，在这种范式中，这些细胞来自一个独特的修复亚群 与上皮组织的细胞正常共存的祖细胞。我们已经展示了它们的存在 修复晶状体和角膜中的细胞。在晶状体中，这些修复祖细胞通过 通过一种独立于DNA复制的机制扩大它们的种群规模，但可能与它们的 多倍体的不寻常的特征。调节祖细胞扩张的信号，它们的 重新编程到修复表型和将修复细胞快速定位到伤口边缘是 未知。虽然修复细胞在损伤部位作为愈合过程的调节器发挥作用，但它们也 有可能转分化为肌成纤维细胞表型，这种细胞类型与纤维化有关。这 Proposal在晶状体和角膜损伤模型中研究了这种新的伤口愈合模式，包括以下几个方面 问题：1)修复祖细胞是造血祖细胞的新后代吗？2)什么是 修复细胞前体细胞在宿主上皮损伤后迅速扩张的机制？ 间充质祖细胞是如何被发出信号迁移到伤口边缘的？ 间充质细胞完成其调节伤口修复的工作后？5)条件是什么？ 诱导修复细胞获得与疾病状态相关的成熟肌成纤维细胞表型 是纤维化吗？这些研究有望在细胞生物学和伤口愈合领域产生重大影响。 通过将伤口愈合调节因子和肌成纤维细胞来源的研究转移到这一新的前体细胞 人口。