The role of mechanical stimulation in macrophage-mediated skeletal muscle regeneration in an in vitro injury model

体外损伤模型中机械刺激在巨噬细胞介导的骨骼肌再生中的作用

• 批准号: 9924240
• 负责人: Stephanie McNamara
• 金额: $ 3.32万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924240
• 关键词: 3-Dimensional; Address; Alternative Therapies; Animal Model; Biological; Biophysics; Cell Communication; Cells; Chronic; Clinical; Clinical Treatment; Contracture; Contusions; Cues; Development; Devices; Exhibits; Extracellular Matrix; Fibrosis; Frequencies; Growth; Immune; Immune response; Immune system; In Vitro; Injury; Investigation; Knowledge; Massage; Mechanical Stimulation; Mechanics; Mediating; Methods; Modeling; Muscle; Muscle Cells; Muscle satellite cell; Natural regeneration; Outcome; Pain; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physical therapy; Play; Process; Recovery; Recovery of Function; Research; Risk; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal muscle injury; Stimulus; Stress; System; Therapeutic; Tissue Engineering; Tissues; Trauma; United States; Validation; Work; cell behavior; chronic pain; design; disability; environmental change; healing; improved; improved functioning; in vitro Model; in vivo; injured; injury and repair; insight; macrophage; mechanical force; muscle regeneration; novel therapeutics; pain reduction; preclinical study; prevent; regenerative; repaired; response; severe injury; side effect; stem cells; success; tissue regeneration; tissue repair; treatment optimization

Project Summary/Abstract Severe muscle injuries resulting from trauma, strain, or contusion are very common yet still present a significant clinical challenge since there is no therapy currently available to restore full function to the damaged tissue. Instead, severe muscle injuries often heal via fibrosis, leading to contracture, pain, and disability. Since skeletal muscle is known to respond strongly to mechanical stimuli, recent studies have shown that the use of mechanical cues alone can effectively stimulate tissue regeneration. Investigation has provided evidence that the immune system, which plays a critical role in tissue repair, may be modulated by mechanical stimulation of the injured tissue. In this proposal, I will focus on investigating the role of mechanical signaling in immune cell-muscle interactions, specifically between macrophages and muscle progenitor cells (MPCs) since macrophages have been shown to play an important role in guiding MPC behavior during repair. I hypothesize that the regenerative effects of macrophages on injured skeletal muscle through their interactions with MPCs will be enhanced under specific conditions of applied cyclic tensile loading leading to improved recovery. I will develop an in vitro model of injured skeletal muscle containing myofibers and MPCs and introduce polarized macrophages into this system. I will design and fabricate a cyclic tensile loading device and use this system to explore the effects of cyclic tensile loading parameters, such as strain and frequency, on macrophage modulation of myofiber regeneration and functional repair of the injured skeletal muscle constructs. I will further evaluate potential mechanisms behind the observed results to understand how mechanical cues may be impacting the interaction between macrophages and MPCs. I hope that the proposed work can offer new insight into how mechanical stimulation can be used clinically as a method of promoting skeletal muscle repair. The knowledge that arises from these studies may enable the optimization of physical therapies to provide better outcomes in the clinical setting and may offer new therapeutic avenues for healing severe muscle injuries.

项目总结/摘要 由创伤、拉伤或挫伤引起的严重肌肉损伤非常常见，但仍存在显著的 临床挑战，因为目前没有治疗可用于恢复受损组织的全部功能。 相反，严重的肌肉损伤往往通过纤维化愈合，导致挛缩，疼痛和残疾。由于骨骼 已知肌肉对机械刺激反应强烈，最近的研究表明，使用机械刺激， 单独的提示可以有效地刺激组织再生。调查提供的证据表明， 在组织修复中起关键作用的神经系统可以通过对损伤的机械刺激来调节 组织.在这个提案中，我将集中研究机械信号在免疫细胞-肌肉中的作用 相互作用，特别是巨噬细胞和肌肉祖细胞（MPC）之间的相互作用，因为巨噬细胞具有 在修复过程中指导MPC行为方面起着重要作用。我假设再生的 巨噬细胞通过与MPCs的相互作用对受损骨骼肌的作用将在 所施加的循环拉伸载荷的特定条件导致改善的恢复。我会建立一个体外模型 含有肌纤维和MPCs的受损骨骼肌，并将极化的巨噬细胞引入其中。 系统我将设计和制作一个循环拉伸加载装置，并使用这个系统来探索的影响， 循环拉伸载荷参数，如应变和频率，对巨噬细胞调节肌纤维 损伤骨骼肌结构的再生和功能修复。我会进一步评估 观察结果背后的机制，以了解机械提示如何影响交互 巨噬细胞和MPC之间的联系我希望，拟议的工作可以提供新的见解，如何机械 刺激可在临床上用作促进骨骼肌修复的方法。所产生的知识 从这些研究中可以优化物理治疗，以提供更好的结果，在临床 并可能为治疗严重的肌肉损伤提供新的治疗途径。