Single-cell transcriptomics identify distinct features of Fibro/Adipogenic Progenitors from healthy and dystrophic muscles


Pre-Clinical Research

Poster Number: 143


Prech Uapinyoying, PhD, National Institutes of Health, Marshall Hogarth, PhD, Childrens Research Institute (CNMC), Surajit Bhattacharya, PhD, Children's National Hospital, Davi Mazala, PhD, Towson University, Karuna Panchapakesan, MS, Children's National Hospital, Carsten Bonnemann, MD, NIH, Jyoti Jaiswal, PhD, Childrens Research Institute (CNMC)

Mononucleate cells residing in skeletal muscle regulate the functionality of multinucleated myofibers at rest and following injury. Mononucleate mesenchymal stem cells (MeSCs) are postnatal stem cells found in adult tissues. Fibro/adipogenic progenitors (FAPs) are amongst such cells found in muscles that are integral to muscle function. To determine the extent of similarity between FAPs and other MeSCs, we have compared these cells at the single cell level using single-cell RNA-seq (scRNA-seq) datasets from multiple mouse tissues. We found FAPs share remarkable transcriptional similarity with MeSCs and identified extracellular proteolysis as a novel FAP-specific biological function. It also established the suitability of PDGFR? as a reliable FAP reporter. Using PDGFR? expression to isolate FAPs from muscles of healthy and dysferlinopathic mouse models, we performed scRNA-seq of FAPs, which identified dysregulated FAP-specific genes. This implicates decreased FAP-mediated Wnt signaling drives FAP dysfunction in dysferlinopathic muscles. Comparison of FAP-specific gene expression in dysferlin- and dystrophin-deficient muscles identified FAP-specific deficits that contribute differently to these diseases. These studies characterize the transcriptomic identity of FAPs, implicate them in regulating muscle physiology by controlling extracellular proteolysis, and show that FAP gene expression is regulated in a disease-specific manner.