Fibroadipogenic progenitor cells as drivers of angiogenesis during muscle regeneration

纤维脂肪祖细胞作为肌肉再生过程中血管生成的驱动因素

基本信息

批准号：
10741438
负责人：
STEVEN S SEGAL
金额：
$ 42.09万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741438
关键词：
Ablation Address Affect Angiogenic Factor Automobile Driving Biocompatible Materials Biology Biopsy Blood Vessels Cell Proliferation Cells Cellular biology Clinical Complement Data Development Disabled Persons Emerging Technologies Emotional Endothelial Cells Event Excision Family Fibroblasts Financial Hardship Goals Growth Histologic Human Hydrogels Image Implant Individual Infiltration Injury Integrin alphaVbeta3 Integrins Intervention Invaded Investments Isometric Contraction Knock-out Laboratories Limb structure LoxP-flanked allele Measures Mediating Methods Microcirculation Modeling Molecular Mus Muscle Muscle Cells Muscle function Muscle satellite cell Muscular Atrophy National Institute of Child Health and Human Development Natural regeneration Outcome Pathway interactions Perfusion Platelet-Derived Growth Factor alpha Receptor Process Proteomics Punch Biopsy Recombinants Recovery Research Project Grants Role Signal Transduction Signaling Molecule Signaling Protein Site Skeletal Muscle System Testing Therapeutic Intervention Thinness Tissue Engineering Tissues Translating Traumatic injury angiogenesis cell type disability engineering design experimental study healing high reward high risk improved intravital microscopy morphogens muscle form muscle regeneration myogenesis novel periostin precursor cell prevent receptor response satellite cell stem cells success therapy design tissue regeneration volumetric muscle loss wound

项目摘要

ABSTRACT Skeletal muscle comprises nearly half of body mass and is subject to traumatic injuries, particularly of the extremities. Damaged muscle mass and function must be restored promptly to minimize physical distortion and prevent long-term disabilities. Furthermore, poor outcomes impose significant emotional and financial burdens on affected individuals and their families. An aspirational goal of the NICHD is to advance the ability to regenerate human limbs by using emerging technologies to activate the body’s own growth pathways and processes. Under most circumstances damaged muscle is efficiently regenerated through a coordinated multicellular response involving muscle stem cells (satellite cells, SCs), endothelial cells (ECs), and fibroblasts or fibroadipogenic precursor cells (FAPs) as well as other resident and infiltrating cell types. However, after the loss of tissue over a critical threshold (volumetric muscle loss, VML), tissue regeneration does not occur and neither mass nor function are regained. The molecular and cellular mechanisms underlying the distinction between subthreshold, regenerating wounds vs. nonregenerating VML are not yet sufficiently understood, posing a critical roadblock to development of translational interventions. A novel punch biopsy model of injury and regeneration developed in the PI’s laboratory using the mouse gluteus maximus muscle highlights the sequential activity of FAPs, ECs, and SCs in successful muscle regeneration. A key observation is that if local FAPs are removed, both angiogenesis and myogenesis fail to occur, making the subthreshold injury instead resemble VML. Whether FAPs effect this relationship by direct actions on ECs, myogenic cells, or both is unknown. Therefore, this research project proposes to: 1) confirm the requirement for FAPs in permitting healing of a subcritical VML injury; 2) test the ability of a candidate molecule, periostin, to rescue microvascular and myofiber regeneration in wounds lacking FAPs; 3) determine whether periostin signals directly to ECs, myogenic cells, or both; and 4) perform an unbiased proteomic screen for additional signaling molecules either secreted directly by FAPs or induced in ECs or myogenic cells by FAPs that may promote the regeneration of intact muscle. These experiments will leverage the team's collective expertise in microvascular imaging, muscle regeneration, FAPs biology, and biomaterials to identify, characterize, and functionally test key cellular and molecular factors differentiating between muscle injuries which heal successfully and those which cannot. If successful, this research project will identify molecules and methods which have the potential to be translated into therapies designed to improve clinical outcomes for disabled individuals, thereby addressing a key unmet need in both basic and applied muscle biology.

抽象的骨骼肌占体重的近一半，容易遭受外伤，尤其是骨骼肌受损的肌肉质量和功能必须立即恢复，以尽量减少身体扭曲和损伤。此外，不良后果会造成严重的情感和经济负担。 NICHD 的一个理想目标是提高受影响个人及其家庭的再生能力。通过使用新兴技术来激活人体自身的生长途径和过程，从而增强人体四肢的功能。大多数情况下，受损的肌肉可以通过协调的多细胞反应有效地再生肌肉干细胞（卫星细胞，SC）、内皮细胞（EC）和成纤维细胞或纤维脂肪形成细胞然而，在组织丢失后，前体细胞（FAP）以及其他驻留细胞和浸润细胞类型。达到临界阈值（体积肌肉损失，VML）时，不会发生组织再生，并且质量和质量都不会发生功能被恢复。阈下之间的区别背后的分子和细胞机制。再生伤口与非再生 VML 尚未得到充分了解，这构成了关键障碍开发了一种新型的损伤和再生穿刺活检模型。 PI 的实验室使用小鼠臀大肌强调了 FAP、EC 和 SC 在成功的肌肉再生中的一个关键观察是，如果局部 FAP 被去除，血管生成就会发生。肌生成失败，使得阈下损伤类似于 VML 是否会影响 FAP。对 EC、生肌细胞或两者的直接作用之间的关系尚不清楚。建议：1) 确认 FAP 允许亚临界 VML 损伤愈合的要求；2) 测试候选分子骨膜素在缺乏微血管和肌纤维再生的伤口中挽救微血管和肌纤维再生的能力 FAP；3) 确定骨膜素是否直接向 EC、肌原细胞或两者发出信号，4) 执行公正的操作；蛋白质组学筛选其他信号分子，这些信号分子由 FAP 直接分泌或在 EC 中诱导，或 FAP 的生肌细胞可能会促进完整肌肉的再生，这些实验将利用这些实验。该团队在微血管成像、肌肉再生、FAP 生物学和生物材料方面的集体专业知识识别、表征和功能测试区分肌肉的关键细胞和分子因素如果成功，该研究项目将识别成功治愈的伤害和无法治愈的伤害。有潜力转化为旨在改善临床的疗法的分子和方法为残疾人士带来成果，从而解决基础肌肉和应用肌肉方面未满足的关键需求生物学。