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: 8161860
• 负责人: A. Sue Menko
• 金额: $ 40.79万
• 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/8161860
• 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

DESCRIPTION (provided by applicant): 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 transdifferentiate 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. PUBLIC HEALTH RELEVANCE: The knowledge gained from our studies of a novel population of progenitor cells, innate to epithelial tissues, that upon wounding are activated to form the repair cells that modulate the wound response, is expected to reveal novel targets for enhancing wound repair and tissue regeneration. Furthermore, our findings that the progeny of these cells also are a principal source of myofibroblasts, a cell type associated with fibrotic diseases such as PCO and corneal scarring, suggest that the results of our studies also will have a major impact on understanding of mechanisms of disease.

描述（由申请人提供）：目前，参与伤口愈合和纤维化的间充质细胞前体的身份仍在争论中。我们提出了一种新的范例，其中这些细胞来自一个独特的修复祖细胞亚群，正常共存的上皮组织的细胞。我们已经证明这些修复细胞存在于透镜和角膜中。在透镜中，这些修复祖细胞通过独立于DNA复制的机制通过扩大其群体大小来快速响应损伤，但可能与其不寻常的多倍性特征有关。介导祖细胞扩增、其重编程为修复表型以及修复细胞快速靶向伤口边缘的信号是未知的。虽然修复细胞在损伤部位作为愈合过程的调节剂发挥作用，但它们也有可能转分化为肌成纤维细胞表型，即与纤维化相关的细胞类型。该提议在透镜和角膜损伤模型中检验了这种新的伤口愈合范例，并提出了以下问题：1）修复祖细胞是造血谱系的新后代吗？2)修复细胞祖细胞对宿主上皮细胞损伤的反应迅速扩增的机制是什么？3)间充质祖细胞是如何向伤口边缘迁移的？4)间充质细胞在完成调节伤口修复的任务后的命运如何？和5）诱导修复细胞获得与疾病状态如纤维化相关的成熟肌成纤维细胞表型的条件是什么？这些研究预计将在细胞生物学和伤口愈合领域产生重大影响，将伤口愈合的调节因子和肌成纤维细胞来源的研究转移到这种新的祖细胞群体。 公共卫生关系：从我们对上皮组织固有的祖细胞的新群体的研究中获得的知识，其在创伤时被激活以形成调节创伤反应的修复细胞，预期将揭示用于增强创伤修复和组织再生的新靶点。此外，我们发现这些细胞的后代也是肌成纤维细胞的主要来源，肌成纤维细胞是一种与纤维化疾病如PCO和角膜瘢痕形成相关的细胞类型，这表明我们的研究结果也将对理解疾病机制产生重大影响。