Impact of intracellular control over macrophage phenotype transitions on angiogenesis and wound healing

细胞内控制巨噬细胞表型转变对血管生成和伤口愈合的影响

• 批准号: 445352816
• 负责人: Dr. Tina Tylek
• 金额: --
• 依托单位: School of Biomedical Engineering, Science and Health Systems
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/445352816?language=en
• 关键词: Impact; intracellular; control; over; macrophage

Impaired wound healing, as in chronic wounds of diabetic conditions, is a major burden of patients and the economic health system. The primary underpinnings of non-healing wounds are a prolonged inflammatory state and defective angiogenesis. Although macrophages, key players of the inflammatory response, are known to regulate angiogenesis, the mechanisms behind how impaired inflammation leads to impaired angiogenesis are not understood. In addition, chronic wounds show a delayed appearance of macrophages of the pro-inflammatory M1 type as well as a diminished recruitment of pro-healing M2 macrophages. However, most studies so far focused only on the importance of M2 type macrophages in wound healing and angiogenesis, and majorly did not consider the importance of the M1 phase for the regulated timeline of their appearance. Thus, it is not known how the delayed M1 presence impacts the subsequent arrival and polarization of M2 macrophages. Therefore, in-depth studies of these processes are needed to enable the design of functional macrophage-based therapies as treatment options for diseases. Recent findings of Dr. Spiller’s group showed that macrophages that undergo a direct transition from M1 macrophages to the M2 type (so-called M1-M2 macrophages) were more angiogenic and less fibrotic than those which differentiated from unactivated M0 macrophages in vitro. In chronic wounds, the deficit of this M1-M2 macrophage type is most likely a major contributor to the observed defective wound healing. Therefore, the overarching goal of this project is to investigate how the transition from M1 to M2 type macrophages affects angiogenic processes in normal and delayed healing. To address this question, a macrophage-based cell therapy strategy will be developed in which engulfed microparticles will be utilized for intracellular control of the transition of pre-polarized M1 macrophages into the M2 type. This strategy may allow for both augmenting the macrophage population and retaining their critical polarization timeline. A 3D tissue-engineered model of vascularization and angiogenesis will determine the effects of the controlled M1-M2 transition on vessel formation and macrophage-endothelial cell interaction in vitro. This translational strategy will be evaluated in vivo in a cutaneous wound model in diabetic and wildtype mice. It is expected that the biomaterial-mediated cell therapy strategy developed in this study will be advantageous for overcoming impaired healing and defective angiogenesis in chronic wounds by augmentation of the pro-healing and pro-angiogenic macrophage phenotype without neglecting the important early inflammatory response. Therefore, the results of this project will be of high clinical relevance.

伤口愈合受损，如糖尿病慢性伤口，是患者和经济卫生系统的主要负担。不愈合伤口的主要基础是长期的炎症状态和有缺陷的血管生成。虽然已知巨噬细胞是炎症反应的关键参与者，可以调节血管生成，但炎症受损导致血管生成受损的机制尚不清楚。此外，慢性伤口显示促炎M1型巨噬细胞的出现延迟以及促愈合M2巨噬细胞的募集减少。然而，目前大多数研究只关注M2型巨噬细胞在伤口愈合和血管生成中的重要性，大多未考虑M1期对其出现的调控时间的重要性。因此，目前尚不清楚M1的延迟存在如何影响M2巨噬细胞的后续到达和极化。因此，需要对这些过程进行深入研究，以设计功能性巨噬细胞为基础的疗法作为疾病的治疗选择。Spiller博士的研究小组最近的发现表明，从M1型巨噬细胞直接转变为M2型巨噬细胞（所谓的M1-M2型巨噬细胞）的巨噬细胞比那些从未活化的M0型巨噬细胞分化出来的巨噬细胞在体外更容易血管生成，纤维化程度更低。在慢性伤口中，这种M1-M2型巨噬细胞的缺失很可能是观察到的伤口愈合缺陷的主要原因。因此，本项目的首要目标是研究从M1型到M2型巨噬细胞的转变如何影响正常和延迟愈合中的血管生成过程。为了解决这个问题，将开发一种基于巨噬细胞的细胞治疗策略，其中吞噬微粒将用于胞内控制预极化M1巨噬细胞向M2型的转变。这种策略既可以增加巨噬细胞的数量，又可以保持它们的临界极化时间。血管形成和血管生成的3D组织工程模型将确定受控M1-M2转化对体外血管形成和巨噬细胞-内皮细胞相互作用的影响。这种转化策略将在糖尿病小鼠和野生型小鼠的皮肤伤口模型中进行体内评估。预计本研究中开发的生物材料介导的细胞治疗策略将有利于通过增强促愈合和促血管生成巨噬细胞表型来克服慢性伤口的愈合受损和血管生成缺陷，而不忽视重要的早期炎症反应。因此，本项目的结果将具有很高的临床相关性。