Uapinyoying Prech, Hogarth Marshall, Battacharya Surajit, Mázala Davi A G, Panchapakesan Karuna, Bönnemann Carsten G, Jaiswal Jyoti K
Center for Genetic Medicine Research, Children's National Research and Innovation Campus, Children's National Hospital, Washington, DC 20012, USA.
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
iScience. 2023 Jul 23;26(8):107479. doi: 10.1016/j.isci.2023.107479. eCollection 2023 Aug 18.
Fibro/adipogenic progenitors (FAPs) are skeletal muscle stromal cells that support regeneration of injured myofibers and their maintenance in healthy muscles. FAPs are related to mesenchymal stem cells (MSCs/MeSCs) found in other adult tissues, but there is poor understanding of the extent of similarity between these cells. Using single-cell RNA sequencing (scRNA-seq) datasets from multiple mouse tissues, we have performed comparative transcriptomic analysis. This identified remarkable transcriptional similarity between FAPs and MeSCs, confirmed the suitability of PDGFRα as a reporter for FAPs, and identified extracellular proteolysis as a new FAP function. Using PDGFRα as a cell surface marker, we isolated FAPs from healthy and dysferlinopathic mouse muscles and performed scRNA-seq analysis. This revealed decreased FAP-mediated Wnt signaling as a potential driver of FAP dysfunction in dysferlinopathic muscles. Analysis of FAPs in dysferlin- and dystrophin-deficient muscles identified a relationship between the nature of muscle pathology and alteration in FAP gene expression.
成纤维/脂肪生成祖细胞（FAPs）是骨骼肌基质细胞，可支持受损肌纤维的再生及其在健康肌肉中的维持。FAPs与在其他成年组织中发现的间充质干细胞（MSCs/MeSCs）相关，但人们对这些细胞之间的相似程度了解甚少。利用来自多个小鼠组织的单细胞RNA测序（scRNA-seq）数据集，我们进行了比较转录组分析。这确定了FAPs和MeSCs之间显著的转录相似性，证实了PDGFRα作为FAPs报告基因的适用性，并确定细胞外蛋白水解是FAPs的一种新功能。使用PDGFRα作为细胞表面标志物，我们从健康和患有dysferlinopathy的小鼠肌肉中分离出FAPs，并进行了scRNA-seq分析。这揭示了FAP介导的Wnt信号传导减少是dysferlinopathy肌肉中FAP功能障碍的潜在驱动因素。对缺乏dysferlin和抗肌萎缩蛋白的肌肉中的FAPs进行分析，确定了肌肉病理学性质与FAP基因表达改变之间的关系。
