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仍在争论中。我们提出了一种新的范式，其中这些细胞来自与上皮组织细胞正常共存的修复祖细胞的独特亚群。我们已经展示了这些修复细胞在晶状体和角膜中的存在。在晶状体中，这些修复祖细胞通过一种独立于DNA复制的机制迅速扩大其群体规模，从而对损伤做出反应，但这可能与它们不寻常的多倍体特征有关。介导祖细胞扩张的信号，它们的重编程到修复表型，以及修复细胞对伤口边缘的快速靶向是未知的。虽然修复细胞在损伤部位作为愈合过程的调节剂起作用，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。本研究在晶状体和角膜损伤模型中探讨了这种新的伤口愈合模式，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)修复细胞祖细胞在宿主上皮损伤后快速扩增的机制是什么？3)间充质祖细胞是如何向创面边缘迁移的？4)间充质细胞完成创伤修复调节功能后的命运如何？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？这些研究有望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。

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.