Inhibition of type I PRMTs reforms muscle stem cell identity enhancing their therapeutic capacity.
MS023
arginine methylation
duchenne muscular dystrophy
mouse
muscle stem cell
regenerative medicine
skeletal muscle
stem cells
type I PRMT
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
07 06 2023
07 06 2023
Historique:
medline:
9
6
2023
pubmed:
7
6
2023
entrez:
7
6
2023
Statut:
epublish
Résumé
In skeletal muscle, muscle stem cells (MuSC) are the main cells responsible for regeneration upon injury. In diseased skeletal muscle, it would be therapeutically advantageous to replace defective MuSCs, or rejuvenate them with drugs to enhance their self-renewal and ensure long-term regenerative potential. One limitation of the replacement approach has been the inability to efficiently expand MuSCs ex vivo, while maintaining their stemness and engraftment abilities. Herein, we show that inhibition of type I protein arginine methyltransferases (PRMTs) with MS023 increases the proliferative capacity of ex vivo cultured MuSCs. Single cell RNA sequencing (scRNAseq) of ex vivo cultured MuSCs revealed the emergence of subpopulations in MS023-treated cells which are defined by elevated Pax7 expression and markers of MuSC quiescence, both features of enhanced self-renewal. Furthermore, the scRNAseq identified MS023-specific subpopulations to be metabolically altered with upregulated glycolysis and oxidative phosphorylation (OxPhos). Transplantation of MuSCs treated with MS023 had a better ability to repopulate the MuSC niche and contributed efficiently to muscle regeneration following injury. Interestingly, the preclinical mouse model of Duchenne muscular dystrophy had increased grip strength with MS023 treatment. Our findings show that inhibition of type I PRMTs increased the proliferation capabilities of MuSCs with altered cellular metabolism, while maintaining their stem-like properties such as self-renewal and engraftment potential.
Identifiants
pubmed: 37285284
doi: 10.7554/eLife.84570
pii: 84570
pmc: PMC10328524
doi:
pii:
Substances chimiques
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
Banques de données
GEO
['GSM5972491', 'GSM5972492', 'GSM5972493', 'GSM5972494']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : FDN-154303
Pays : Canada
Informations de copyright
© 2023, Dominici et al.
Déclaration de conflit d'intérêts
CD, OV, JD, EH, YW, IR, JJ, ND, SR No competing interests declared
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