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.

蝾螈是哺乳动物的近亲之一，它们保留了完全的再生能力。 在他们的一生中。Eguchi等人，证明蝾螈的透镜 在16年的时间里反复摘除了18次，最后一个透镜再生为 和第一次一样完美。考虑到人类有很高的风险，蝾螈的这种能力是显着的。 在单次白内障手术后发生后囊膜混浊。结果我们 几十年来一直认为蝾螈不会患纤维化疾病。然而，我们的初步数据显示， 表明巨噬细胞的消耗不仅阻止了透镜的再生，而且还诱导了 蝾螈眼睛单一损伤后的纤维样反应。我们还发现， 抗炎药地塞米松阻止了透镜再生，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， 在蝾螈的再生过程中，它们有着独特的功能。根据我们的初步数据和工作 我们的假设是，炎症是触发虹膜色素沉着所必需的， 上皮（IPE）细胞重编程和巨噬细胞限制了炎症 损伤部位的可能性。因此，巨噬细胞的缺乏将与 对由不受控制的炎症引起的损伤的纤维化反应触发募集， 肌成纤维细胞的分化和异常的细胞外基质沉积。测试这些 假设，我们将描述炎症反应的幅度和持续时间， 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细胞重编程的标志物。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表型的转变 反应最后，将进一步研究巨噬细胞耗竭诱导的纤维化损伤类型。 其特点以及可能的机制导致其形成。最近在小鼠和 人类已经证明了巨噬细胞功能的固有可塑性， 通过操纵它们的局部微环境来编程。我们的长期目标是 描述蝾螈微环境中指示蝾螈抗纤维化反应的因素 巨噬细胞，可能能够引发类似的功能，在人类巨噬细胞作为一个 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