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: 9759304
• 负责人: Stephanie McNamara
• 金额: $ 3.51万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759304
• 关键词: Address; Alternative Therapies; Animal Model; Biological; Biophysics; Cell Communication; Cells; Chronic; Clinical; Clinical Treatment; Contracture; Contusions; Cues; Development; Devices; Dimensions; 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; Stem cells; 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; insight; macrophage; mechanical force; muscle regeneration; novel therapeutics; pain reduction; preclinical study; prevent; regenerative; repaired; response; side effect; 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.

项目摘要/摘要 由创伤、拉伤或挫伤引起的严重肌肉损伤是非常常见的，但仍然存在显著的 临床挑战，因为目前还没有治疗方法可以恢复受损组织的全部功能。 相反，严重的肌肉损伤通常通过纤维化愈合，导致痉挛、疼痛和残疾。因为骨骼 众所周知，肌肉对机械刺激反应强烈，最近的研究表明，机械刺激的使用 光是线索就能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系统可能会受到损伤机械刺激的调节 组织。在这项提案中，我将重点研究机械信号在免疫细胞肌肉中的作用。 巨噬细胞和肌祖细胞(MPC)之间的相互作用，因为巨噬细胞 已被证明在修复过程中引导MPC行为方面发挥着重要作用。我假设再生体 巨噬细胞通过与MPC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可提高恢复率。我将开发一种体外模型 损伤的含有肌纤维和MPC的骨骼肌，并将极化的巨噬细胞引入 系统。我将设计和制作一种循环拉伸加载装置，并使用该系统来探索 应变和频率等循环拉伸加载参数对巨噬细胞对肌纤维调节的影响 受损骨骼肌构筑的再生和功能修复。我会进一步评估潜力 观察结果背后的机制，以了解机械提示可能如何影响交互作用 巨噬细胞和巨噬细胞之间。我希望这项拟议的工作能提供新的视角，让人们了解机械 刺激在临床上可以作为促进骨骼肌修复的一种方法。由此产生的知识 这些研究可能使物理治疗的最优化在临床上提供更好的结果 并可能为治疗严重的肌肉损伤提供新的治疗途径。