Preservation of Limbal Stem Cell Function in Corneal Injury

角膜损伤后角膜缘干细胞功能的保存

• 批准号: 10224209
• 负责人: Heather Chandler
• 金额: $ 39.77万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224209
• 关键词: Ablation; Acute; Animal Model; Aqueous Humor; Binding; Biochemical; Biological Process; Blindness; Blood Circulation; Blood Vessels; Burn injury; Cardiovascular Diseases; Cell Lineage; Cell membrane; Chemistry; Chronic; Cicatrix; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cornea; Corneal Diseases; Corneal Injury; Development; Disease; Dose; Engineering; Epithelial; Epithelial Cells; Exhibits; Fibroblasts; Fibrosis; Film; Formulation; Genes; Genetic; Goblet Cells; Health; Health Promotion; Homeostasis; Human; Imaging Device; Infiltration; Injury; Integumentary system; Longevity; Mediating; Membrane; Modeling; Molecular; Mus; Muscle; Mutagenesis; Myofibroblast; Myopathy; Natural regeneration; Ocular Physiology; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Outcomes Research; Pathologic; Pathology; Pharmacology; Physiological; Prevention; Process; Production; Protein Family; Proteins; Protocols documentation; Rattus; Recombinants; Regenerative capacity; Research; Role; Safety; Serum; Signal Transduction; Stress; TRIM Family; Techniques; Testing; Thinness; Tissues; Topical application; Transforming Growth Factor beta; Trauma; Vascularization; alkalinity; angiogenesis; biochemical tools; cell injury; combat; corneal epithelial wound healing; corneal epithelium; corneal regeneration; corneal repair; corneal scar; effective therapy; epithelium regeneration; experimental study; extracellular; gene repair; healing; improved; improved outcome; in vivo; injury and repair; limbal; live cell imaging; migration; mouse model; novel; novel therapeutics; oxidative damage; preservation; regenerative tissue; repaired; response; scale up; stem; stem cell function; stem cell niche; stem cell proliferation; stem cells; synergism; tissue injury; tissue regeneration; tissue repair; wound; wound healing

Project Summary Corneal wound healing is a complex and coordinated process involving injury repair to the epithelial layer and stimulation of limbal stem cell (LSC) proliferation for tissue regeneration. Prevention of excessive stromal myofibroblast activation and vascular ingrowth is also imperative to avoid fibrosis and angiogenesis, which can compromise transparency of the cornea. An approach that can functionally target multiple steps in corneal wound healing may have the potential to significantly improve healing outcomes, leading to novel therapeutic options. This project stems from our novel findings that reveal a vital role for MG53, a tissue repair gene, in modulating LSC function associated with corneal injury-repair. We show that genetic ablation of MG53 leads to injury-induced corneal epithelial thinning, conjunctivalization, stromal fibrosis, and vascularization, all hallmarks of limbal stem cell deficiency (LSCD). Mice with sustained elevation of MG53 in circulation show increased tissue regenerative capacity with enhanced LSC function. MG53 is present in the human tear film, aqueous humor, and corneal epithelial cells, supporting its potential function in corneal homeostasis and wound healing. Using in vivo corneal injury models, we find that MG53 promotes corneal transparency by facilitating epithelial viability and reducing post-injury fibrosis and vascularization. Experiments outlined in this project are centered on testing the hypothesis that MG53 constitutes an active component of the corneal injury- repair and regeneration by maintaining the health of LSCs, as well as controlling the fibrotic response of stromal fibroblasts. We envision that pharmacological formulation to enhance the synergy between MG53 delivery, LSC function, and fibrotic control could be a potentially effective means to treat corneal diseases. The outcome of this research shall have significant translational value in developing potentially effective therapies to treat corneal injury and fibrosis associated with corneal disease.

项目摘要 角膜伤口愈合是一个复杂而协调的过程，涉及到上皮的损伤修复。 以及刺激角膜缘干细胞(LSC)增殖以促进组织再生。防止过度使用 间质肌成纤维细胞的激活和血管内长也是避免纤维化和血管生成的必要条件。 这可能会影响角膜的透明度。一种可以在功能上针对多个步骤的方法 在角膜伤口愈合方面可能有显著改善愈合结果的潜力，导致新的 治疗选择。这个项目源于我们的新发现，揭示了MG53在组织修复中的重要作用 基因，在调节与角膜损伤修复相关的LSC功能。我们证明了MG53的遗传消融 导致损伤所致的角膜上皮变薄、结膜形成、间质纤维化和血管形成，所有这些 角膜缘干细胞缺乏(LSCD)的特征。循环中MG53持续升高的小鼠显示 增强LSC功能，增强组织再生能力。MG53存在于人类泪膜中， 房水和角膜上皮细胞，支持其在角膜动态平衡和 伤口愈合。利用活体角膜损伤模型，我们发现MG53通过 促进上皮细胞存活，减少损伤后纤维化和血管形成。这篇文章中概述的实验 项目的中心是测试MG53构成角膜损伤的活性成分的假设- 通过维持LSCs的健康以及控制LSCs的纤维化反应来修复和再生 间质成纤维细胞。我们设想，该药物配方将增强MG53之间的协同作用 交付、LSC功能和纤维化控制可能是治疗角膜疾病的一种潜在的有效手段。这个 这项研究的结果在开发潜在有效的治疗方法方面具有重要的翻译价值 用于治疗与角膜疾病相关的角膜损伤和纤维化。