Paradigms of Wound Healing and Fibrosis in the Eye

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正在争论中。我们提出了一种新的范式，在这种模式中，这些细胞来自与上皮组织细胞正常共存的修复前体细胞的独特亚群。我们已经证明了这些修复细胞在晶状体和角膜中的存在。在晶状体中，这些修复前体细胞通过一种独立于DNA复制的机制扩大其种群规模，从而对损伤做出快速反应，但可能与它们不同寻常的多倍体特征有关。调节祖细胞扩增、其重编程为修复表型以及修复细胞快速定位于伤口边缘的信号尚不清楚。虽然修复细胞在损伤部位作为愈合过程的调节细胞发挥作用，但它们也有可能转分化为肌纤维母细胞表型，这种细胞类型与纤维化有关。这项建议在晶状体和角膜损伤模型中研究了这种新的创伤修复模式，提出了以下问题：1)修复前体细胞是造血祖细胞的新后代吗？2)修复细胞前体细胞响应宿主上皮损伤而迅速扩张的机制是什么？3)间充质前体细胞是如何被告知迁移到伤口边缘的？4)间充质细胞完成其调节伤口修复的工作后的命运是什么？以及5)诱导修复细胞获得与纤维化等疾病状态相关的成熟肌成纤维细胞表型的条件是什么？这些研究有望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祖细胞群体，在细胞生物学和伤口愈合领域产生重大影响。 公共卫生相关性：我们对一组新的祖细胞的研究获得的知识，这些祖细胞是上皮组织固有的，在创伤时被激活，形成调节伤口反应的修复细胞，有望揭示促进伤口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后发性白内障和角膜瘢痕形成等纤维化疾病相关的细胞类型，这表明我们的研究结果也将对理解疾病的机制产生重大影响。

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.