Mechanisms of functional skeletal muscle repair: critical role of matrix associated IL-33

功能性骨骼肌修复机制：基质相关 IL-33 的关键作用

• 批准号: 10335123
• 负责人: Stephen F. Badylak
• 金额: $ 48.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335123
• 关键词: Acute; Animal Model; Atrophic; Biological; Bypass; Cell Differentiation process; Cell Nucleus; Cell physiology; Cells; Chromatin; Cicatrix; Cohort Studies; Data; Deposition; Development; Diagnostic; Encapsulated; Event; Excision; Experimental Designs; Extracellular Matrix; Extracellular Matrix Degradation; Family member; Gene Expression; Genes; Human; Hydrogels; Immune; Immune response; Immunobiology; Inflammation; Inflammatory; Injury; Interdisciplinary Study; Interleukin-1; Interleukin-13; Interleukin-4; Interleukins; Knock-out; Lead; Lipid Binding; Lung; Macrophage Activation; Mediating; Mediator of activation protein; Membrane Lipids; Molecular; Mus; Muscle; Myeloid Cells; Myocardium; Natural regeneration; Nuclear; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Population; Process; Prognostic Marker; Proteins; Proteomics; Receptor Signaling; Regenerative Medicine; Regenerative capacity; Regulatory T-Lymphocyte; Role; STAT6 gene; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Skeletal muscle injury; Skin repair; Source; Stromal Cells; Supporting Cell; Testing; Therapeutic; Tissue Engineering; Tissues; Trauma; Tumor-infiltrating immune cells; base; bioscaffold; cardiac repair; design; epithelial repair; experience; improved outcome; insight; macrophage; muscle regeneration; myogenesis; nanovesicle; next generation; novel therapeutics; oxidation; pre-clinical; preclinical study; receptor; regeneration following injury; regenerative; regenerative tissue; repaired; response; response to injury; scaffold; spatiotemporal; therapeutic biomarker; therapeutic target; trafficking; transcriptomics; tumor; uptake; volumetric muscle loss

ABSTRACT Skeletal muscle is inherently regenerative following acute injury. It is well established that the spatiotemporal dynamics of the responding immune cell populations are critical determinants of the regenerative process. Specifically, an appropriately timed switch from a type-I to a type-II immune response is required for skeletal muscle regeneration following injury, and this self-regenerative capacity is lost after a critical size volumetric muscle loss (VML) event such as trauma or tumor excision. We recently showed that an acellular biologic scaffold composed entirely of extracellular matrix (ECM) can facilitate a macrophage phenotype transition that leads to downstream site-appropriate functional tissue deposition and myogenesis as a treatment for volumetric muscle loss in preclinical animal models and in 13 human patients. Our current objective is to gain translatable mechanistic insights into the immunobiology behind both normal skeletal muscle regeneration following acute injury and in the presence of an ECM bioscaffold with the broad aim of developing therapeutics that enable and direct immune cells to facilitate constructive, functional remodeling after VML. The proposed studies will investigate the ability and necessity of a newly identified component of the ECM, the interleukin-33 (IL-33), to influence remodeling after skeletal muscle injury. Typically found in the nucleus of stromal cells, IL-33 has been shown to be a potent mediator of skeletal muscle, cardiac muscle, lung epithelium, and dermal repair via poorly defined mechanisms involving immune cells expressing the IL-33 receptor, ST2. The subject matter of the present proposal is based upon our discovery that IL-33 is stably integrated into the ECM via encapsulation within matrix bound nanovesicles (MBV) thereby protecting IL-33 from rapid oxidation. Following ECM degradation, MBV are released from the matrix, taken up by immune cells wherein IL-33 activates macrophages towards a pro-remodeling phenotype via a non-canonical ST2-indendent pathway. The discovery of IL-33 as an integral component of ECM-MBV represents a distinct therapeutic target and marker of tissue remodeling. Furthermore, our experimental design will allow for the first in-depth molecular characterization of the genes and signaling pathways regulated by the ST2-independent IL-33 pathway and will greatly advance our understanding of the molecular mechanisms by which ECM facilitates the functional remodeling response. Separately, the use of ECM therapies (either as a hydrogel as is presently being tested in a Phase I clinical trial by Ventrix for cardiac repair) or as a bioscaffold sheet (recently used as a treatment for VML in a 13 patient cohort study) can now be studied from a new perspective, and will help guide the design of next generation products, diagnostics and therapeutic applications.

摘要 骨骼肌在急性损伤后具有固有的再生能力。已经确定的是，时空 应答免疫细胞种群的动态是再生过程的关键决定因素。 具体地说，骨骼需要从I型免疫反应到II型免疫反应的适当时机的切换 损伤后肌肉再生，这种自我再生能力在达到临界体积后丧失 肌肉丧失(VML)事件，如创伤或肿瘤切除。我们最近发现了一种脱细胞生物支架 完全由细胞外基质(ECM)组成的细胞可促进巨噬细胞表型转变，从而导致 下游部位适宜的功能组织沉积和肌肉生成治疗体积肌 在临床前动物模型和13名人类患者中丢失。我们目前的目标是获得可翻译的 急性心肌梗死后正常骨骼肌再生背后的免疫生物学机制 并在ECM生物支架存在的情况下，开发治疗方法，使 引导免疫细胞促进VML后的建设性、功能性重塑。拟议的研究将 调查一种新发现的细胞外基质成分--白介素33(IL-33)的能力和必要性 影响骨骼肌损伤后的重塑。IL-33通常存在于基质细胞的细胞核中，一直以来 被证明是骨骼肌、心肌、肺上皮和皮肤修复的有效介体。 明确了免疫细胞表达IL-33受体ST2的机制。会议的主题是 目前的建议是基于我们的发现，IL-33通过封装稳定地整合到ECM中 在基质结合的纳米微囊(MBV)内，从而保护IL-33免受快速氧化。遵循ECM 降解时，MBV从基质中释放出来，由免疫细胞摄取，其中IL-33激活巨噬细胞 通过一条非规范的ST2-缩进途径向促重塑表型转变。白介素33的发现是一种 ECM-MBV的组成成分代表了独特的治疗靶点和组织标志物 改建。此外，我们的实验设计将允许第一次深入的分子表征 ST2非依赖的IL-33途径调控的基因和信号通路将大大促进 我们对ECM促进功能重塑反应的分子机制的理解。 另外，ECM疗法的使用(作为水凝胶，目前正在I期临床试验中测试 Ventrix用于心脏修复)或生物支架(最近用于治疗13例VML患者 队列研究)现在可以从一个新的角度进行研究，并将有助于指导下一代的设计 产品、诊断和治疗应用。

项目成果

Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition.

• DOI: 10.1038/s41536-024-00346-2
• 发表时间: 2024-01-27
• 期刊: NPJ REGENERATIVE MEDICINE
• 影响因子: 7.2
• 作者: Bartolacci, J. G.;Behun, M. N.;Warunek, J. P.;Li, T.;Sahu, A.;Dwyer, G. K.;Lucas, A.;Rong, J.;Ambrosio, F.;Turnquist, H. R.;Badylak, S. F.
• 通讯作者: Badylak, S. F.

Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes.

• DOI: 10.3389/fimmu.2021.611910
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Dwyer GK;Turnquist HR
• 通讯作者: Turnquist HR

Neuro-epithelial-ILC2 crosstalk in barrier tissues.

• DOI: 10.1016/j.it.2022.09.006
• 发表时间: 2022-10
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Ziyi Yin;Y. Zhou;H. Turnquist;Quan Liu

Vitamin B-reath easier: vitamin B6 derivatives reduce IL-33 to limit lung inflammation.

维生素 B 更容易：维生素 B6 衍生物可降低 IL-33 以限制肺部炎症。

• DOI: 10.1038/s41423-023-01076-z
• 发表时间: 2023
• 期刊: Cellular & molecular immunology
• 影响因子: 24.1
• 作者: Turnquist,HēthR