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Single cell RNA sequencing of human FAPs reveals different functional stages in Duchenne muscular dystrophy

Lookup NU author(s): Esther Fernández-SimónORCiD, Rasya Gokul Nath, Adrienne Unsworth, Dr Marianela Schiava, Professor Giorgio TascaORCiD, Dr Rachel Queen, Daniel CoxORCiD, Professor Jordi Diaz ManeraORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Copyright © 2024 Fernández-Simón, Piñol-Jurado, Gokul-Nath, Unsworth, Alonso-Pérez, Schiava, Nascimento, Tasca, Queen, Cox, Suarez-Calvet and Díaz-Manera.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.


Publication metadata

Author(s): Fernandez-Simon E, Pinol-Jurado P, Gokul-Nath R, Unsworth A, Alonso-Perez J, Schiava M, Nascimento A, Tasca G, Queen R, Cox D, Suarez-Calvet X, Diaz-Manera J

Publication type: Article

Publication status: Published

Journal: Frontiers in Cell and Developmental Biology

Year: 2024

Volume: 12

Online publication date: 09/07/2024

Acceptance date: 03/06/2024

Date deposited: 05/08/2024

ISSN (electronic): 2296-634X

Publisher: Frontiers Media SA

URL: https://doi.org/10.3389/fcell.2024.1399319

DOI: 10.3389/fcell.2024.1399319

Data Access Statement: The data presented in the study are deposited in the Single cell Broadinstitute.org repository, accession number SCP2678, available at: https://singlecell.broadinstitute.org/single_cell/study/SCP2678/single-cell-rna-sequencing-of-human-faps.


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Funding

Funder referenceFunder name
#202034-10
Academy of Medical Sciences Professorship Scheme
AFM
AFM-24341
APR4/1007
Fundación Isabel Gemio
MR/W019086/1
La Marató de TV3
Medical Research Council

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