Identifying the interactions between fibro-adipogenic progenitors and the extracellular matrix in skeletal muscle fibrosis

确定骨骼肌纤维化中纤维脂肪祖细胞和细胞外基质之间的相互作用

• 批准号: 10678267
• 负责人: Taryn Loomis
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678267
• 关键词: Affect; Angiopoietins; Animals; Architecture; Behavior; Biopsy Specimen; Blood Vessels; Cell Adhesion Molecules; Cell Nucleus; Cell Separation; Cells; Chronic; Coculture Techniques; Collagen; Communication; Contracture; Data; Deposition; Development; Duchenne muscular dystrophy; Engineering; Environment; Extracellular Matrix; Extracellular Structure; Fibrosis; Goals; Heterogeneity; Human; Hydrogels; Impairment; Individual; Injury; Mechanics; Methods; Modeling; Mus; Muscle; Muscle Cells; Muscle function; Muscle satellite cell; Myofibroblast; Myopathy; Natural regeneration; Nuclear Protein; Pathologic; Pattern; Phenotype; Play; Population; Proteins; Research Project Grants; Role; Sampling; Signal Pathway; Signal Transduction; Skeletal Muscle; Source; Structure; Symptoms; Testing; Therapeutic; Up-Regulation; Work; antifibrotic treatment; crosslink; density; differential expression; improved; innovation; insight; mdx mouse; mechanical signal; mechanotransduction; mouse model; muscle regeneration; myogenesis; progenitor; receptor; regenerative; response; response to injury; small molecule inhibitor; stem cell differentiation; stem cells; success; therapeutic target; tool; transcription factor

Project Summary/Abstract Fibrosis is a consequence of a myriad of skeletal muscle diseases including Duchenne muscular dystrophy. Fibrosis is the pathological accumulation of extracellular matrix (ECM) and impairs muscle function resulting in a loss of mobility and significant reduction in strength. Muscle resident fibro-adipogenic progenitors (FAPs) are the key source of ECM deposition in skeletal muscle. Pro-regenerative FAPs support regeneration by activating in response to injury, depositing ECM to replace the damaged matrix, and releasing pro-myogenic signals. However, in the context of fibrosis, there is a significant upregulation of a more pro-fibrotic FAP subpopulation. FAPs activate into myofibroblasts and remain at chronically high levels, leading to excess ECM deposition. What drives the development of a fibrotic versus regenerative FAP phenotype is not well understood. The mechanics and architecture of the ECM is altered in fibrotic muscle compared to healthy muscle, providing mechanical cues to surrounding cells. FAPs are known to be sensitive to these changes in mechanics and architecture, however, what drives this signaling pathway is not understood. Yes-associated protein (YAP) is strongly correlated with FAP activation into myofibroblasts on stiff substrates. Blocking YAP activity is a potential method to manipulate FAP-ECM signaling and reduce myofibroblast activation in the context of fibrosis. ECM signaling to FAPs may also influence the heterogeneity of FAPs, with the levels of pro- regenerative and pro-fibrotic FAPs changing during injury and fibrosis. How the subpopulations of FAPs may be contributing to ECM deposition in fibrosis and regeneration is not well understood. Elucidating the differential role of FAP subpopulations provides specific targets for anti-fibrotic and pro-myogenic therapies. Our central hypothesis is that blocking FAPs’ sensitivity to stiff substrates through inhibition of YAP will reduce the number of pro-fibrotic FAPs resulting in ECM deposition that promotes myogenesis. We will test our central hypothesis via two aims. In Aim 1, we will inhibit YAP activity in order to determine its role in FAPs’ sensitivity to engineered matrix substrates mimicking the mechanical and architectural features of healthy and fibrotic ECM. In Aim 2, we will determine the differences in ECM deposition from pro-fibrotic and pro- regenerative FAPs and its role on myogenesis to assess how the heterogeneity with the FAP population affects the development of fibrosis and regeneration. Success in these aims will identify the interactions between FAPs and the ECM in the context of fibrosis, which can be used as targets for anti-fibrotic therapies.

项目摘要/摘要 纤维化是多种骨骼肌疾病的结果，包括杜氏肌营养不良症。 纤维化是细胞外基质(ECM)的病理性积聚，并损害肌肉功能，导致 失去机动性和力量的显著减弱。肌内纤维成脂前体细胞(FAP)是 骨骼肌细胞外基质沉积的主要来源。支持再生的FAP通过以下方式支持再生 损伤后激活，沉积ECM以替代受损的基质，并释放促肌原 信号。然而，在纤维化的背景下，有一个更有利于纤维化的FAP显著上调 亚群。FAP激活成肌成纤维细胞，并保持在长期高水平，导致细胞外基质过剩 证词。是什么推动了纤维化与再生性FAP表型的发展？ 明白了。与健康肌肉相比，纤维化肌肉细胞外基质的机制和结构发生了改变。 肌肉，为周围的细胞提供机械信号。众所周知，FAP对这些变化非常敏感 然而，驱动这一信号通路的机制和架构尚不清楚。是-关联 蛋白质(YAP)与FAP在僵硬底物上激活成肌成纤维细胞密切相关。阻止Yap 活性是一种潜在的方法来操纵FAP-ECM信号和减少肌成纤维细胞的激活 纤维化的背景。ECM对FAP的信号传导也可能影响FAP的异质性，其PRO水平与FAP的异质性密切相关。 再生和促纤维化FAP在损伤和纤维化过程中的变化。FAP的亚群如何 在纤维化和再生中促进ECM沉积的机制尚不清楚。澄清 FAP亚群的不同作用为抗纤维化和促肌源性治疗提供了特异性靶点。 我们的中心假设是，通过抑制YAP来阻断FAP对刚性底物的敏感性将 减少促纤维化FAP的数量，导致ECM沉积，促进肌肉生成。我们将测试我们的 中心假说有两个目的。在目标1中，我们将抑制YAP活性，以确定其在FAP中的作用 对工程基质基材的敏感度，模仿健康和 纤维性ECM。在目标2中，我们将确定促肝纤维化和促肝纤维化的ECM沉积的差异。 再生FAP及其在肌肉发生中的作用评估FAP群体的异质性 影响纤维化和再生的发展。成功实现这些目标将确定相互作用 在纤维化的背景下，FAP和ECM之间的相互作用，可以作为抗纤维化治疗的靶点。