Single cell RNA sequencing of human FAPs reveals different functional stages in Duchenne muscular dystrophy
Fernández Simón, Esther (John Walton Muscular Dystrophy Research Centre)
Piñol-Jurado, Patricia (John Walton Muscular Dystrophy Research Centre)
Gokul-Nath, R. (John Walton Muscular Dystrophy Research Centre)
Alonso Pérez, Jorge (Newcastle University)
Schiava, M. (John Walton Muscular Dystrophy Research Centre)
Nascimento, A. (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Tasca, Giorgio (John Walton Muscular Dystrophy Research Centre)
Cox, D. (John Walton Muscular Dystrophy Research Centre)
Diaz-Manera, Jordi (Institut de Recerca Sant Pau)
Unsworth, Adrienne (John Walton Muscular Dystrophy Research Centre)
Queen, Rachel (John Walton Muscular Dystrophy Research Centre)
Suarez-Calvet, Xavier (Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife))
Universitat Autònoma de Barcelona. Departament de Medicina

Date:	2024
Abstract:	Background: Duchenne muscular dystrophy is a genetic disease produced by mutations in the dystrophin gene characterized by early onset muscle weakness leading to severe and irreversible disability. Muscle degeneration involves a complex interplay between multiple cell lineages spatially located within areas of damage, termed the degenerative niche, including inflammatory cells, satellite cells (SCs) and fibro-adipogenic precursor cells (FAPs). FAPs are mesenchymal stem cell which have a pivotal role in muscle homeostasis as they can either promote muscle regeneration or contribute to muscle degeneration by expanding fibrotic and fatty tissue. Although it has been described that FAPs could have a different behavior in DMD patients than in healthy controls, the molecular pathways regulating their function as well as their gene expression profile are unknown. Methods: We used single-cell RNA sequencing (scRNAseq) with 10X Genomics and Illumina technology to elucidate the differences in the transcriptional profile of isolated FAPs from healthy and DMD patients. Results: Gene signatures in FAPs from both groups revealed transcriptional differences. Seurat analysis categorized cell clusters as proliferative FAPs, regulatory FAPs, inflammatory FAPs, and myofibroblasts. Differentially expressed genes (DEGs) between healthy and DMD FAPs included upregulated genes CHI3L1, EFEMP1, MFAP5, and TGFBR2 in DMD. Functional analysis highlighted distinctions in system development, wound healing, and cytoskeletal organization in control FAPs, while extracellular organization, degradation, and collagen degradation were upregulated in DMD FAPs. Validation of DEGs in additional samples (n = 9) using qPCR reinforced the specific impact of pathological settings on FAP heterogeneity, reflecting their distinct contribution to fibro or fatty degeneration in vivo. Conclusion: Using the single-cell RNA seq from human samples provide new opportunities to study cellular coordination to further understand the regulation of muscle homeostasis and degeneration that occurs in muscular dystrophies.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	adipogenesis ; fibro-adipogenic progenitor cells ; fibrosis ; muscle dystrophies ; single cell RNA sequencing
Published in:	Frontiers in Cell and Developmental Biology, Vol. 12 (2024) , art. 1399319, ISSN 2296-634X

DOI: 10.3389/fcell.2024.1399319
PMID: 39045456

11 p, 2.3 MB

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