Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-12-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202317405 |
| _version_ | 1797226514637389824 |
|---|---|
| author | Francesca Florio Sara Vencato Filomena T Papa Michela Libergoli Eyemen Kheir Imen Ghzaiel Thomas A Rando Yvan Torrente Stefano Biressi |
| author_facet | Francesca Florio Sara Vencato Filomena T Papa Michela Libergoli Eyemen Kheir Imen Ghzaiel Thomas A Rando Yvan Torrente Stefano Biressi |
| author_sort | Francesca Florio |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T02:12:05Z |
| format | Article |
| id | doaj.art-c9912217f8cc4e60b7661bc54ca1d39c |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T14:26:07Z |
| publishDate | 2023-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-c9912217f8cc4e60b7661bc54ca1d39c2024-04-03T04:45:17ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-12-011512n/an/a10.15252/emmm.202317405Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscleFrancesca Florio0Sara Vencato1Filomena T Papa2Michela Libergoli3Eyemen Kheir4Imen Ghzaiel5Thomas A Rando6Yvan Torrente7Stefano Biressi8Department of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento ItalyDepartment of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento ItalyDepartment of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento ItalyDepartment of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento ItalyDepartment of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento ItalyDepartment of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento ItalyBroad Stem Cell Research Center University of California Los Angeles Los Angeles CA USANeurology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan ItalyDepartment of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento ItalyAbstract 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.https://doi.org/10.15252/emmm.202317405complement C1 complexDuchenne muscular dystrophyfibro‐adipogenic progenitorsfibrosisskeletal muscle regeneration |
| spellingShingle | Francesca Florio Sara Vencato Filomena T Papa Michela Libergoli Eyemen Kheir Imen Ghzaiel Thomas A Rando Yvan Torrente Stefano Biressi Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle EMBO Molecular Medicine complement C1 complex Duchenne muscular dystrophy fibro‐adipogenic progenitors fibrosis skeletal muscle regeneration |
| title | Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle |
| title_full | Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle |
| title_fullStr | Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle |
| title_full_unstemmed | Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle |
| title_short | Combinatorial activation of the WNT‐dependent fibrogenic program by distinct complement subunits in dystrophic muscle |
| title_sort | combinatorial activation of the wnt dependent fibrogenic program by distinct complement subunits in dystrophic muscle |
| topic | complement C1 complex Duchenne muscular dystrophy fibro‐adipogenic progenitors fibrosis skeletal muscle regeneration |
| url | https://doi.org/10.15252/emmm.202317405 |
| work_keys_str_mv | AT francescaflorio combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT saravencato combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT filomenatpapa combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT michelalibergoli combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT eyemenkheir combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT imenghzaiel combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT thomasarando combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT yvantorrente combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle AT stefanobiressi combinatorialactivationofthewntdependentfibrogenicprogrambydistinctcomplementsubunitsindystrophicmuscle |