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: 10705582
• 负责人: Katia Del Rio-Tsonis
• 金额: $ 18.06万
• 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/10705582
• 关键词: Adopted; Adult; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Apoptosis; Behavior; Cataract Extraction; Cell Reprogramming; 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; Macrophage; Mammals; Methods; Modeling; Mus; Myofibroblast; Natural regeneration; Nature; Newts; Operative Surgical Procedures; Oryctolagus cuniculus; Pharmaceutical Preparations; Phenotype; Pigment Epithelium; Play; Prevention strategy; Proliferating; Rattus; Regenerative response; Regimen; Research; Resolution; Role; Signal Transduction; Site; TNF gene; Testing; Tissues; Work; Zebrafish; capsule; epithelial to mesenchymal transition; healing; high risk; inflammatory marker; information gathering; lens; lens regeneration; migration; novel strategies; preservation; prevent; progenitor; recruit; regenerative; response; response to injury; restraint; stem; tissue regeneration; treatment strategy; wound healing; Adopted; Adult; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Apoptosis; Behavior; Cataract Extraction; Cell Reprogramming; 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; Macrophage; Mammals; Methods; Modeling; Mus; Myofibroblast; Natural regeneration; Nature; Newts; Operative Surgical Procedures; Oryctolagus cuniculus; Pharmaceutical Preparations; Phenotype; Pigment Epithelium; Play; Prevention strategy; Proliferating; Rattus; Regenerative response; Regimen; Research; Resolution; Role; Signal Transduction; Site; TNF gene; Testing; Tissues; Work; Zebrafish; capsule; epithelial to mesenchymal transition; healing; high risk; inflammatory marker; information gathering; lens; lens regeneration; migration; novel strategies; preservation; prevent; progenitor; 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.

Newts是保持哺乳动物最接近的亲戚之一，可保留完整的再生能力 整个一生。 eguchi等人证明了纽特的镜头可能是 在16年的过程中反复删除18次，最后一个镜头再生为 完全是第一个。考虑到人类的风险很高，纽特的这种能力非常出色 单次白内障手术后发生后囊的不透明。结果，我们 几十年来，纽特对纤维化疾病无关。但是，我们的初步数据 证明巨噬细胞的耗竭不仅阻止了晶状体再生，而且还诱导了 纽特眼中一次受伤后的纤维化反应。我们还发现用 抗炎药物塞米松防止了晶状体再生，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防止纤维化中的真正独特作用 疾病。这也表明，尽管炎症和巨噬细胞是必需的 在纽特的再生中，它们具有独特的功能。根据我们的初步数据和工作 在斑马鱼中完成的假设是触发虹膜色素需要炎症 上皮（IPE）细胞重编程，并在炎症上限制巨噬细胞 受伤部位的潜力。因此，没有巨噬细胞将与 不受控制的炎症触发招募和 肌纤维细胞和异常细胞外基质沉积的分化。测试这些 假设，我们将表征炎症反应的大小和持续时间 Newt Eye，地塞米松和巨噬细胞耗竭对IPE细胞凋亡的影响， IPE细胞重编程的增殖和标记。我们还将描述巨噬细胞 极化状态及其在炎症过程中从M1到M2表型的过渡 回复。最后，将进一步 表征以及可能导致其形成的可能机制。在小鼠和 人类表现出巨噬细胞功能的固有可塑性，因为它们是高度的 通过操纵当地微环境来编程。我们的长期目标是 表征了NEWT微环境中的因素，该因素指导了Newt的抗纤维化反应 可以在人类巨噬细胞中引起相似功能的巨噬细胞 纤维化疾病的治疗或预防策略。