Inflammation is a driver of newt lens regeneration

炎症是蝾螈晶状体再生的驱动因素

• 批准号: 10433462
• 负责人: Katia Del Rio-Tsonis
• 金额: $ 21.68万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433462
• 关键词: Adopted; Adult; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Apoptosis; Behavior; Cataract Extraction; Characteristics; Data; Deposition; Dexamethasone; Disease; Dorsal; Epithelial Cells; Extracellular Matrix; Eye; Fibrosis; Gene Expression; Genes; Goals; Human; Human Pathology; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Iris; Light; Mammals; Methods; Modeling; Mus; Myofibroblast; Natural regeneration; Nature; Newts; Operative Surgical Procedures; Oryctolagus cuniculus; Pharmaceutical Preparations; Phenotype; Pigment Epithelium; Play; Prevention strategy; Proliferation Marker; Rattus; Regenerative response; Regimen; Research; Resolution; Role; Shock; Signal Transduction; Site; TNF gene; Testing; Time; Tissues; Work; Zebrafish; base; capsule; epithelial to mesenchymal transition; healing; high risk; inflammatory marker; lens; lens regeneration; macrophage; migration; novel strategies; preservation; prevent; progenitor; programs; recruit; regenerative; response; response to injury; restraint; stem; tissue regeneration; treatment strategy; wound healing

Newts are one of the closest living relatives to mammals that retain full regenerative capabilities throughout their entire lifetime. Eguchi et al., demonstrated that the lens of the newt could be repeatedly removed 18 times over the course of 16 years and the last lens regenerated as perfectly as the first. This ability in newts is remarkable considering that humans have a high risk of developing posterior capsule opacification after a single cataract surgery. As a result, we thought for decades that newts were impervious to fibrotic disease. However, our preliminary data demonstrates macrophage depletion not only prevented lens regeneration but it also induced a fibrotic-like response after a single injury in the newt eye. We also found that treatment with the anti-inflammatory drug dexamethasone prevented lens regeneration but failed to induce a fibrotic response to injury. This highlights a truly unique role of the newt macrophage in preventing fibrotic disease. It also suggests that while inflammation and macrophages are necessary for regeneration in the newt, they have unique functions. Based on our preliminary data and work done in zebrafish, our hypothesis is that inflammation is required to trigger iris pigmented epithelial (IPE) cell reprogramming and that macrophages place limits on the inflammatory potential of the injury site. Thereby the absence of macrophages would be associated with a fibrotic response to injury resulting from uncontrolled inflammation triggering the recruitment and differentiation of myofibroblasts and aberrant extracellular matrix deposition. To test these hypotheses, we will characterize the magnitude and duration of the inflammatory response in the newt eye, the impact of dexamethasone and macrophage depletion on IPE cell apoptosis, proliferation, and markers of IPE cell reprogramming. We will also characterize macrophage polarization states and their transition from M1 to M2 phenotypes during the inflammatory response. Finally, the type of fibrotic injury induced by macrophage depletion will be further characterized as well as possible mechanisms leading to its formation. Recent work in mice and humans has demonstrated an inherent plasticity in macrophage function since they are highly programmable through manipulation of their local microenvironment. Our long term goal is to characterize factors in the newt microenvironment that instruct an anti-fibrotic response from newt macrophages that could be capable of eliciting similar functions in human macrophages as a treatment or prevention strategy for fibrotic diseases.

蝾螈是与哺乳动物最接近的近亲之一，它们具有完全的再生能力。 在他们的一生中。江口等人的研究表明，水貂的晶状体可以 在16年的时间里反复取出18次，最后一次晶状体再生为 和第一次一样完美。考虑到人类有很高的风险，蝾螈的这种能力是值得注意的 单次白内障手术后后囊混浊的发生率。因此，我们 几十年来，人们一直认为蝾螈对纤维性疾病是免疫的。然而，我们的初步数据 表明巨噬细胞的耗尽不仅阻止了晶状体再生，而且还诱导了 单一眼球损伤后的纤维性反应。我们还发现，使用 抗炎药地塞米松阻止晶状体再生但未能诱导纤维化 对伤害的反应。这突出了纽特巨噬细胞在预防纤维化方面真正独特的作用。 疾病。它还表明，虽然炎症和巨噬细胞是必要的 在蝾螈的再生中，它们具有独特的功能。根据我们的初步数据和工作 在斑马鱼身上做的实验，我们的假设是炎症是引发虹膜色素沉着的必要条件 上皮(IPE)细胞重编程和巨噬细胞对炎症的限制 受伤部位的潜在危险。因此，巨噬细胞的缺失将与 对损伤的纤维化反应是由于失控的炎症引发的募集和 肌成纤维细胞分化和异常细胞外基质沉积。为了测试这些 假设，我们将表征炎症反应的大小和持续时间 Newt Eyes，地塞米松和巨噬细胞去除对IPE细胞凋亡的影响， 增殖和IPE细胞重编程的标志物。我们还将描述巨噬细胞的特征 炎症过程中偏振态及其从M1表型向M2表型的转变 回应。最后，巨噬细胞耗竭引起的纤维化损伤的类型将进一步 其特点以及导致其形成的可能机制。小鼠和小鼠的最新研究 人类在巨噬细胞功能上表现出一种固有的可塑性，因为它们高度 通过操纵当地的微环境进行编程。我们的长期目标是 纽特微环境中指示纽特抗纤维化反应的因素的特征 巨噬细胞能够在人类巨噬细胞中引发类似的功能 纤维化疾病的治疗或预防策略。