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

基本信息

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
项目类别：
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

项目摘要

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当这些损伤涉及体积肌肉损失（VML）时，当前的黄金标准手术是治疗。然而，自体肌瓣移植或游离组织移植会导致明显的纤维化和脂肪浸润，受损。再生、慢性疼痛和严重的长期功能障碍。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。在临床前 VML 模型的出版物中，我们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我们现在提供初步证据，表明在临界尺寸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，FAP 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然而，在慢性肌肉病理学中，如肌营养不良症，FAP 可以分化为纤维化和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 会发生变化。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。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。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 – 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 的临床治疗奠定了基础。