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

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.

蝾螈是现存与哺乳动物关系最近的亲戚之一，保留了完全的再生能力 在他们的一生中。 Eguchi等人证明蝾螈的晶状体可以 在16年的时间里被反复摘除18次，最后一个镜片再生为 完美地作为第一个。考虑到人类具有很高的风险，蝾螈的这种能力是非凡的 单次白内障手术后出现后囊混浊的情况。结果，我们 几十年来，人们一直认为蝾螈不会受到纤维化疾病的影响。不过，我们的初步数据 表明巨噬细胞耗竭不仅阻止了晶状体再生，而且还诱导了 蝾螈眼睛受到一次损伤后出现类似纤维化的反应。我们还发现，用 抗炎药地塞米松可阻止晶状体再生，但未能诱导纤维化 对伤害的反应。这凸显了蝾螈巨噬细胞在预防纤维化方面的真正独特作用 疾病。它还表明，虽然炎症和巨噬细胞对于 在蝾螈的再生过程中，它们具有独特的功能。根据我们的初步数据和工作 在斑马鱼中进行，我们的假设是炎症需要触发虹膜色素 上皮（IPE）细胞重编程和巨噬细胞限制炎症 损伤部位的潜力。因此，巨噬细胞的缺失与 对由不受控制的炎症引发的损伤引起的纤维化反应引发募集和 肌成纤维细胞的分化和异常的细胞外基质沉积。为了测试这些 假设，我们将描述炎症反应的强度和持续时间 蝾螈眼，地塞米松和巨噬细胞耗竭对 IPE 细胞凋亡的影响， 增殖和 IPE 细胞重编程标记。我们还将表征巨噬细胞 炎症过程中的极化状态及其从 M1 到 M2 表型的转变 回复。最后，巨噬细胞耗竭引起的纤维化损伤的类型将进一步 特征以及导致其形成的可能机制。最近在小鼠和 人类已表现出巨噬细胞功能的固有可塑性，因为它们高度 通过操纵局部微环境进行编程。我们的长期目标是 表征蝾螈微环境中指导蝾螈抗纤维化反应的因素 巨噬细胞能够引发与人类巨噬细胞类似的功能 纤维化疾病的治疗或预防策略。

项目成果

Isolation and Characterization of Peritoneal Macrophages from Salamanders.

蝾螈腹膜巨噬细胞的分离和表征。

• DOI: 10.1007/978-1-0716-2659-7_18
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Sallese,Anthony;Tsissios,Georgios;Pérez-Estrada,JRaúl;Martinez,Arielle;DelRio-Tsonis,Katia
• 通讯作者: DelRio-Tsonis,Katia