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Interdependency of fibroadipogenic progenitors and extracellular matrix that drive skeletal muscle fibrosis

驱动骨骼肌纤维化的纤维脂肪祖细胞和细胞外基质的相互依赖性

基本信息

批准号：
10602460
负责人：
LUCAS R SMITH
金额：
$ 46.18万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-05 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602460
关键词：
Adopted Apoptosis Apoptotic Architecture Area Biocompatible Materials Biopsy Cells Clinical Coculture Techniques Collagen Collagen Fiber Communication Contracts Contracture Defect Development Duchenne muscular dystrophy Dystrophin Engineering Environment Excision Extracellular Matrix Feedback Fibrillar Collagen Fibrosis Gel Genetic Transcription Health Human Impairment In Situ Infusion procedures Injections Injury Interruption Investigation Joints Knowledge Mechanics Mesenchymal Cell Neoplasm Methodology Monitor Mouse Strains Mus Muscle Muscle function Muscle rehabilitation Muscle satellite cell Muscular Dystrophies Myofibroblast Myopathy Natural regeneration Pathologic Pathology Phenotype Prior Therapy Production Profibrotic signal Proliferating Property Regulation Research Role Signal Transduction Skeletal Muscle Stretching Structure System Testing Tissues Treatment Efficacy Variant Weight-Bearing state Work antifibrotic treatment crosslink density functional decline functional improvement functional restoration gene therapy in vivo innovation lipid biosynthesis mdx mouse mechanical properties mechanical signal mesenchymal stromal cell micro-dystrophin mouse model muscle regeneration muscle stiffness myogenesis novel prevent progenitor regeneration following injury regeneration function regenerative repaired response restoration stem cells success targeted treatment therapy development

项目摘要

PROJECT SUMMARY Fibrosis is the accumulation of extracellular matrix components that disrupt tissue function and is prevalent across many muscle diseases. Muscle functions compromised in fibrosis include muscles primary function to contract as well as its ability to be compliantly stretched when not active. This results in weak and stiff muscle decreasing mobility and producing joint contractures. Skeletal muscle regenerates following injury from resident muscle stem cells, however those cells are sensitive to the organization and mechanics of fibrotic extracellular matrix. Another muscle resident stem cell, fibro-adipogenic progenitors, support myogenesis following injury, but in the context of fibrosis contribute to the pathologic buildup of extracellular matrix. However, the sensitivity of fibro-adipogenic progenitors to their mechanical environment is unknown. Nor is it known how fibro-adipogenic progenitors production of extracellular matrix signals to muscle stem cells to support or impair myogenesis. In order to target effective anti-fbrotic therapies the mechanisms that of communication between fibro-adipogenic progenitors and the extracellular matrix that defines fibrosis must be revealed. Further, the fibrotic environment can act as a barrier to restorative gene therapies for muscular dystrophy, but how fibrosis may influence the efficacy of promising gene therapies is unknown. Fibrosis is particularly common in Duchenne muscular dystrophy, with associated joint contractures. Yet, even removal of functional dystrophin from more fibrotic mouse strains yields a less severe fibrosis, motivating a conjunction of studies in both mice and humans. Fibro-adipogenic progenitors can be activated into pro- fibrogenic cells to resist apoptotic signals and produce excessive extracellular matrix components. This fibrotic extracellular matrix is mainly made of fibrillar collagen, which is the dominant load-bearing structure within healthy and fibrotic extracellular matrix. However, the organization of collagen fibers in the extracellular matrix can alter both the mechanics and adherent cell phenotypes. Fibro-adipogenic progenitors are similar to mesenchymal stromal cells, yet how extracellular matrix organization and mechanical signals drive conversion to the pro-fibrotic state are not known. Nor is it known how one of the primary functions of fibro-adipogenic progenitors, to secrete extracellular matrix, impacts the muscle stem cells responsible for myogenesis. This the potential to create a positive feedback cycle between fibro-adipogenic protenitors and the extracellular matrix. Promising gene therapy using micro-dystrophin is able to largely restore the integrity of myofibers. However, it isn’t known if once the pro-fibrotic cycle is in place if restoring the myofiber integrity and the initiating signals of fibrosis will be sufficient to reverse prominent fibrosis and the associated decline in function. Thus, our objective is to reveal fibro-adipogenic progenitors-based extracellular matrix contribution to functional decline and lack of regeneration in fibrosis along with the potential to reverse fibrosis in muscular dystrophy. In Aim 1, we will utilize a combination of engineered gels and native decellularized matrices to mimic health and fibrosis to determine both the architectural and mechanical features of a cell substrate that directs fibro- adipogenic progenitor fate. In Aim 2, we will induce pro-fibrotic or pro-regenerative fibro-adipogenic progenitor synthesis of extracellular matrices to determine how their structure influences muscle stem cell myogenesis in fibrosis. In Aim 3, micro-dystrophin gene therapy will be administered to before and after the onset of fibrosis to stratify the functional efficacy and change in fibrosis based on the initial stage of fibro-adipogenic progenitors and fibrosis. Success in these Aims will establish the mechanisms fibro-adipogenic progenitors and extracellular matrix interact to perpetuate progressive fibrosis and identify specific targets for anti-fibrotic therapy development that can restore function and enhance the efficacy of restorative gene therapy in muscular dystrophies.

项目摘要纤维化是细胞外基质成分的积累，破坏组织功能，许多肌肉疾病。纤维化中受损的肌肉功能包括肌肉的主要功能，收缩以及其在不活动时顺应性伸展的能力。这导致肌肉无力和僵硬降低活动性并产生关节挛缩。居民受伤后骨骼肌再生肌肉干细胞，然而，这些细胞对纤维化细胞外基质的组织和力学敏感，矩阵另一种肌肉驻留干细胞，纤维脂肪生成祖细胞，支持损伤后的肌生成，但在纤维化的情况下，导致细胞外基质的病理性积聚。然而，纤维脂肪生成祖细胞与其机械环境的关系尚不清楚。也不知道纤维脂肪形成祖细胞产生细胞外基质信号给肌肉干细胞以支持或损害肌生成。在为了靶向有效的抗纤维化治疗，祖细胞和定义纤维化的细胞外基质必须被揭示。此外，纤维化环境可以作为肌营养不良症恢复性基因治疗的障碍，但是纤维化如何影响肌营养不良症的恢复性基因治疗，有希望的基因疗法的功效是未知的。纤维化在杜氏肌营养不良症中特别常见，伴有相关的关节挛缩。但即使从纤维化程度更高的小鼠品系中去除功能性肌营养不良蛋白，产生不太严重的纤维化，结合小鼠和人类的研究。纤维脂肪生成祖细胞可以被激活成前脂肪细胞，纤维化细胞抵抗凋亡信号并产生过量的细胞外基质成分。这种纤维化细胞外基质主要由纤维状胶原组成，这是细胞内的主要承重结构。健康和纤维化细胞外基质。然而，细胞外基质中胶原纤维的组织可以改变力学和粘附细胞表型。纤维成脂祖细胞类似于间充质基质细胞，然而细胞外基质组织和机械信号如何驱动转化到促纤维化状态是未知的。也不知道纤维脂肪形成的主要功能之一是如何祖细胞分泌细胞外基质，影响负责肌生成的肌肉干细胞。这个有可能在纤维脂肪生成蛋白和细胞外基质之间产生正反馈循环。使用微肌营养不良蛋白的有前途的基因治疗能够在很大程度上恢复肌纤维的完整性。但目前尚不清楚一旦促纤维化周期到位，如果恢复肌纤维的完整性和启动信号，纤维化将足以逆转显著的纤维化和相关的功能下降。因此，我们的目标是揭示基于纤维脂肪形成祖细胞的细胞外基质对功能下降和缺乏纤维化的再生沿着逆转肌营养不良症纤维化的潜力。在目标1中，我们将利用工程凝胶和天然脱细胞基质的组合来模拟健康和纤维化，以确定指导纤维化的细胞基质的结构和机械特征，成脂祖细胞命运。在目标2中，我们将诱导促纤维化或促再生纤维脂肪形成祖细胞，细胞外基质的合成，以确定它们的结构如何影响肌肉干细胞的成肌作用，纤维化在目标3中，将在纤维化发生之前和之后进行微小肌营养不良蛋白基因治疗，根据纤维-脂肪形成祖细胞的初始阶段对功能功效和纤维化变化进行分层和纤维化。这些目标的成功将建立纤维脂肪生成祖细胞和细胞外基质的机制。基质相互作用，使进行性纤维化永久化，并确定抗纤维化治疗开发的特定靶点可以恢复功能并增强肌营养不良症恢复性基因治疗的功效。