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.

抽象的 急性损伤后，骨骼肌本质上是再生的。众所周知的是时空 反应免疫细胞种群的动力学是再生过程的关键决定因素。 具体而言，骨骼需要适当的定时开关，从I型到II型免疫反应 受伤后的肌肉再生，并且这种自我再生能力在临界大小后会损失 肌肉丧失（VML）事件，例如创伤或肿瘤切除。我们最近表明一个细胞生物支架 完全由细胞外基质（ECM）组成，可以促进巨噬细胞表型过渡 适合位点的功能组织沉积和肌发生作为体积肌肉的治疗 临床前动物模型和13例人类患者的损失。我们目前的目标是获得可翻译的 急性后两种正常骨骼肌再生背后的免疫生物学的机械洞察力 受伤和ECM生物苏斯科托管的存在，其广泛的目的是开发可实现和 直接免疫细胞促进VML后建设性的功能重塑。拟议的研究将 研究ECM新近识别成分的能力和必要性，即白介素33（IL-33） 骨骼肌损伤后影响重塑。 IL-33通常在基质细胞的细胞核中发现 证明是骨骼肌，心肌，肺上皮和皮肤修复的有效介体 涉及表达IL-33受体的免疫细胞的定义机制，ST2。主题 目前的建议基于我们发现，IL-33通过封装稳定地整合到ECM中 在基质结合的纳米接受者（MBV）中，从而保护IL-33免受快速氧化的影响。遵循ECM 降解，MBV从基质中释放出来，由免疫细胞收集，其中IL-33激活巨噬细胞 通过非典型的ST2引入途径迈向亲塑死的表型。发现IL-33作为一个 ECM-MBV的整体成分代表了组织的独特治疗靶标和标记 重塑。此外，我们的实验设计将允许对 由独立于ST2的IL-33途径调节的基因和信号通路，将大大推进 我们对ECM促进功能重塑响应的分子机制的理解。 另外，使用ECM疗法（要么作为水凝胶作为目前在I期临床试验中进行测试的水凝胶 通过ventrix进行心脏修复）或作为生物效果纸（最近用作13名患者的VML治疗 同类研究）现在可以从新的角度研究，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

Editorial: Beyond Histocompatibility - Understanding the Non-MHC Determinants Shaping Transplantation Outcome and Tolerance Induction.

• DOI: 10.3389/fimmu.2021.759706
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Byersdorfer CA;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