Single-cell transcriptomic analysis of the identity and function of fibro/adipogenic progenitors in healthy and dystrophic muscle
Prech Uapinyoying,
Marshall Hogarth,
Surajit Battacharya,
Davi A.G. Mázala,
Karuna Panchapakesan,
Carsten G. Bönnemann,
Jyoti K. Jaiswal
Affiliations
Prech Uapinyoying
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
Marshall Hogarth
Center for Genetic Medicine Research, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA
Surajit Battacharya
Center for Genetic Medicine Research, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA
Davi A.G. Mázala
Center for Genetic Medicine Research, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA; Department of Kinesiology, College of Health Professions, Towson University, Towson, MD 21252, USA
Karuna Panchapakesan
Center for Genetic Medicine Research, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA
Carsten G. Bönnemann
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Jyoti K. Jaiswal
Center for Genetic Medicine Research, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA; Department of Genomics and Precision Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA; Corresponding author
Summary: 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.
