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

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

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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.

抽象的涉及大组织损失的肢体创伤对一般和军事都带来了重大的临床挑战人群。当这些伤害涉及体积肌肉损失（VML）时，当前的金标准手术就是治疗肌肉皮瓣自体移植或自由组织转移。然而，这些导致纤维化和脂肪浸润的显着障碍再生，慢性疼痛和重大的长期功能障碍。目前有根本缺乏了解全厚度，非常尺寸的VML的敌对环境中的分子和细胞过程导致纤维化和不良愈合结果的缺陷，无论治疗方法如何。在最近的一系列临床前VML模型中的出版物，我们的小组定义了临界大小阈值观察到VML标志：纤维化和脂肪浸润，慢性炎症以及跨整个肌纤维桥接缺点。现在，我们提供了初步证据，表明在批判尺寸的细胞反应中存在明显且失调的细胞反应纤维辅助祖细胞（FAP）快速增殖的缺陷。 FAP是动态的间充质基质细胞在肌肉干细胞（也称为卫星细胞）的肌肉干细胞（MUSC）中起着关键的支持和协调作用再生;但是，在慢性肌肉病理中，例如肌肉营养不良，FAP可以区分成纤维化和在一个被认为是由巨噬细胞和M2巨噬细胞的特定子集引导的过程中的成脂谱系。该提案的总体目的是通过工程进行免疫调节来再生功能性肌肉生物材料系统将FAP引导到促增再生成状态，从而创建环境利基向导 MUSC移植和肌肉再生。我们的中心假设认为VML损伤后，本地FAP 经历直接区分为纤维化和脂肪组织的异常表型的过渡促进脂质介质的传递将解决这些FAP并恢复MUSC的再生潜力。我们提案以下目的：目标1：确定异常FAP在脂肪浸润和纤维化中的作用 VML受伤。目标2：评估M2极化巨噬细胞在FAP上增加促纤维信号传导的贡献在VML中的功能。 AIM 3：测试PEG-4MAL水凝胶中的促进性FAP和MUSC是否共递送 VML后增强肌肉再生和功能恢复。影响 - VML是一个普遍的临床挑战即使在黄金标准自体后治疗后，功能性结果也很差。我们将定义免疫和FAP的关键作用在此过程中的细胞并制定新设计的免疫调节和再生治疗策略为转化为VML的临床治疗提供基础。