Engineering the Immune and Fibrotic Response in Volumetric Muscle Loss

设计体积肌肉损失中的免疫和纤维化反应

• 批准号: 10705119
• 负责人: Nick J Willett
• 金额: $ 32.73万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705119
• 关键词: Adipose tissue; Animals; Attenuated; Autologous Transplantation; Biocompatible Materials; CXCR4 gene; Cell Count; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell Transplantation; Cell physiology; Cells; Characteristics; Chronic; Clinical; Clinical Treatment; Coculture Techniques; Cytometry; Data; Defect; Development; Encapsulated; Engineering; Engraftment; Environment; Fibrosis; Foundations; Functional Regeneration; Gait; General Population; Goals; Histology; Hydrogels; Immune; Impairment; In Vitro; Infiltration; Inflammation; Injury; Integrins; Interleukin-10; Interleukin-4; Isometric Exercise; Lead; Liposomes; Macrophage; Maleimides; Military Personnel; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Muscle satellite cell; Muscular Dystrophies; Myeloid Cells; Natural regeneration; Operative Surgical Procedures; Outcome; Pathologic Processes; Pathology; Phenotype; Play; Polyethylene Glycols; Pre-Clinical Model; Process; Production; Profibrotic signal; Proliferating; Publications; Recovery of Function; Role; Saline; Series; Signal Transduction; Sorting; Stem cell transplant; System; Testing; Thick; Time; Tissue Engineering; Tissues; Torque; Transgenic Animals; Translating; Transplantation; Treatment Efficacy; Work; analytical method; cell type; chronic pain; controlled release; directed differentiation; experimental study; functional disability; functional improvement; functional outcomes; healing; immunoengineering; immunomodulatory therapies; immunoregulation; in vivo; limb injury; lipid mediator; mesenchymal stromal cell; monocyte; muscle engineering; muscle regeneration; myogenesis; novel; novel therapeutic intervention; pre-clinical; quadriceps muscle; regeneration potential; regenerative; regenerative treatment; repaired; response; satellite cell; scaffold; stem cell function; stem cell niche; stem cell proliferation; stem cells; treatment strategy; volumetric muscle loss

ABSTRACT Extremity trauma involving large tissue loss presents a significant clinical challenge for both general and military populations. When these injuries involve Volumetric Muscle Loss (VML), the current gold standard surgery is treatment with muscle flap autografts or free tissue transfer. However, these result in significant fibrosis and fatty infiltration, impaired regeneration, chronic pain, and significant long-term functional disabilities. There is currently a fundamental lack of understanding of the molecular and cellular processes in the hostile environment of a full thickness, critically sized VML defect which leads to the fibrotic and poor healing outcomes regardless of the treatment approach. In a series of recent publications in pre-clinical VML models, our group has defined the critical size threshold above which the characteristic VML hallmarks are observed: fibrosis and fatty infiltration, chronic inflammation, and lack of myofiber bridging across the defect. We now present preliminary evidence that there is a distinct and dysregulated cellular response in the critically sized defect with rapid proliferation of fibro-adipogenic progenitor cells (FAPs). FAPs are a dynamic mesenchymal stromal cells that play a critical support and coordination role for muscle stem cells, also known as satellite cells (MuSCs), during regeneration; however, in chronic muscle pathologies, like muscular dystrophies, FAPs can differentiate into fibrotic and adipogenic lineages in a process that is thought to be directed by macrophages and specific subsets of M2 macrophages. The overall objective of this proposal is to regenerate functional muscle after VML by engineering an immunomodulatory biomaterial system to direct the FAPs towards a pro-regenerative state, thus creating an environmental niche conducive to MuSCs transplantation and muscle regeneration. Our central hypothesis posits that following VML injury, local FAPs undergo a transition to an aberrant phenotype that directly differentiates into fibrotic and fatty tissue and that controlled delivery of pro-resolving lipid mediators will resolve these FAPs and restore the regenerative potential of MuSCs. We propose the following aims: Aim 1: To determine the role of aberrant FAPs in fatty infiltration and fibrosis associated with VML injuries. Aim 2: To assess the contribution of increased pro-fibrotic signaling of M2 polarized macrophages on FAPs function in VML. Aim 3: To test whether co-delivery of pro-regenerative FAPs and MuSC within PEG-4MAL hydrogel enhance muscle regeneration and functional recovery following VML. Impact – VML is a pervasive clinical challenge with poor functional outcomes even after gold standard autograft treatment. We will define the critical roles of immune and FAP cells in this process and develop newly engineered immunomodulatory and regenerative treatment strategies that will provide a foundation to translate into clinical treatments for VML.

抽象的 涉及大量组织损失的四肢创伤对一般和军事人员来说都是一个重大的临床挑战 人口。当这些损伤涉及体积肌肉损失 (VML) 时，当前的金标准手术是治疗 自体肌瓣移植或游离组织移植。然而，这些会导致显着的纤维化和脂肪浸润，损害 再生、慢性疼痛和严重的长期功能障碍。目前还存在根本性的缺乏 了解全厚度、临界尺寸 VML 的恶劣环境中的分子和细胞过程 无论采用何种治疗方法，都会导致纤维化和愈合结果不佳的缺陷。在最近的一系列 在临床前 VML 模型的出版物中，我们的小组定义了临界尺寸阈值，超过该阈值特征 观察到 VML 特征：纤维化和脂肪浸润、慢性炎症以及缺乏肌纤维桥接 缺点。我们现在提出初步证据表明，在临界尺寸的细胞中存在明显且失调的细胞反应。 纤维脂肪祖细胞（FAP）快速增殖的缺陷。 FAPs是一种动态的间充质基质细胞 在肌肉干细胞（也称为卫星细胞（MuSC））的过程中发挥关键的支持和协调作用 再生;然而，在慢性肌肉病变中，如肌营养不良症，FAP 可以分化为纤维化和肌营养不良。 脂肪形成谱系被认为是由巨噬细胞和 M2 巨噬细胞的特定子集引导的。 该提案的总体目标是通过设计免疫调节剂在 VML 后再生功能性肌肉 生物材料系统引导 FAP 进入促再生状态，从而创造一个有利于 FAP 的环境生态位 MuSC 移植和肌肉再生。我们的中心假设认为，VML 损伤后，局部 FAP 经历向异常表型的转变，直接分化为纤维化和脂肪组织并控制 递送促溶解脂质介质将溶解这些 FAP 并恢复 MuSC 的再生潜力。我们 提出以下目标： 目标 1：确定异常 FAP 在脂肪浸润和纤维化中的作用 VML 损伤。目标 2：评估 M2 极化巨噬细胞促纤维化信号增强对 FAP 的贡献 VML 中的函数。目标 3：测试 PEG-4MAL 水凝胶中是否共同递送促再生 FAP 和 MuSC 增强 VML 后的肌肉再生和功能恢复。影响 – VML 是一项普遍的临床挑战 即使在金标准自体移植治疗后，功能结果也不佳。我们将定义免疫和 FAP 的关键作用 细胞在此过程中并开发新设计的免疫调节和再生治疗策略，这将 为转化为 VML 的临床治疗奠定基础。