Fibrosis is associated with compromised muscle functionality in Duchenne muscular dystrophy (DMD). We report observations with tissues from dystrophic patients and mice supporting a model to explain fibrosis in DMD, which relies on the crosstalk between the complement and the WNT signaling pathways and the functional interactions of two cellular types. Fibro-adipogenic progenitors and macrophages, which populate the inflamed dystrophic muscles, act as a combinatorial source of WNT activity by secreting distinct subunits of the C1 complement complex. The resulting aberrant activation of the WNT signaling in responsive cells, such as fibro-adipogenic progenitors, contributes to fibrosis. Indeed, pharmacological inhibition of the C1r/s subunits in a murine model of DMD mitigated the activation of the WNT signaling pathway, reduced the fibrogenic characteristics of the fibro-adipogenic progenitors, and ameliorated the dystrophic phenotype. These studies shed new light on the molecular and cellular mechanisms responsible for fibrosis in muscular dystrophy and open to new therapeutic strategies.

Combinatorial activation of the WNT-dependent fibrogenic program by distinct complement subunits in dystrophic muscle / Florio, Francesca; Vencato, Sara; Papa, Filomena T; Libergoli, Michela; Kheir, Eyemen; Ghzaiel, Imen; Rando, Thomas A; Torrente, Yvan; Biressi, Stefano. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 2023, 15:12(2023), pp. 1-20. [10.15252/emmm.202317405]

Combinatorial activation of the WNT-dependent fibrogenic program by distinct complement subunits in dystrophic muscle

Florio, Francesca;Papa, Filomena T;Libergoli, Michela;Kheir, Eyemen;Biressi, Stefano
2023-01-01

Abstract

Fibrosis is associated with compromised muscle functionality in Duchenne muscular dystrophy (DMD). We report observations with tissues from dystrophic patients and mice supporting a model to explain fibrosis in DMD, which relies on the crosstalk between the complement and the WNT signaling pathways and the functional interactions of two cellular types. Fibro-adipogenic progenitors and macrophages, which populate the inflamed dystrophic muscles, act as a combinatorial source of WNT activity by secreting distinct subunits of the C1 complement complex. The resulting aberrant activation of the WNT signaling in responsive cells, such as fibro-adipogenic progenitors, contributes to fibrosis. Indeed, pharmacological inhibition of the C1r/s subunits in a murine model of DMD mitigated the activation of the WNT signaling pathway, reduced the fibrogenic characteristics of the fibro-adipogenic progenitors, and ameliorated the dystrophic phenotype. These studies shed new light on the molecular and cellular mechanisms responsible for fibrosis in muscular dystrophy and open to new therapeutic strategies.
2023
12
Florio, Francesca; Vencato, Sara; Papa, Filomena T; Libergoli, Michela; Kheir, Eyemen; Ghzaiel, Imen; Rando, Thomas A; Torrente, Yvan; Biressi, Stefan...espandi
Combinatorial activation of the WNT-dependent fibrogenic program by distinct complement subunits in dystrophic muscle / Florio, Francesca; Vencato, Sara; Papa, Filomena T; Libergoli, Michela; Kheir, Eyemen; Ghzaiel, Imen; Rando, Thomas A; Torrente, Yvan; Biressi, Stefano. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 2023, 15:12(2023), pp. 1-20. [10.15252/emmm.202317405]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/398650
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