Connexin43 gap junction drives fascia mobilization and repair of deep skin wounds

•Gap junction protein Connexin43 (Cx43) is upregulated in fascia fibroblasts that are responsible for scar formation.•Inhibition of Cx43 reduces scar formation.•Cx43 inhibition disrupts calcium oscillations in fibroblasts.•Cx43 is required for the collective migration of fascia fibroblasts and the m...

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Bibliographic Details
Published in:Matrix biology 2021-03, Vol.97, p.58-71
Main Authors: Wan, Li, Jiang, Dongsheng, Correa-Gallegos, Donovan, Ramesh, Pushkar, Zhao, Jiakuan, Ye, Haifeng, Zhu, Shaohua, Wannemacher, Juliane, Volz, Thomas, Rinkevich, Yuval
Format: Article
Language:English
Subjects:
Calcium signalling
Cell interactions
Connexin 43
Extracellular matrix
Fascia
Fibroblasts
Fibrosis
Scars
Skin
Wound healing
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Summary:•Gap junction protein Connexin43 (Cx43) is upregulated in fascia fibroblasts that are responsible for scar formation.•Inhibition of Cx43 reduces scar formation.•Cx43 inhibition disrupts calcium oscillations in fibroblasts.•Cx43 is required for the collective migration of fascia fibroblasts and the mobilization of fascia matrix into wounds. Deep and voluminous skin wounds are repaired with scars, by mobilization of fibroblasts and extracellular matrix from fascia, deep below the skin. The molecular trigger of this novel repair mechanism is incompletely understood. Here we reveal that the gap junction alpha-1 protein (Connexin43, Cx43) is the key to patch repair of deep wounds. By combining full-thickness wound models with fibroblast lineage specific transgenic lines, we show Cx43 expression is substantially upregulated in specialized fibroblasts of the fascia deep beneath the skin that are responsible for scar formation. Using live imaging of fascia fibroblasts and fate tracing of the fascia extracellular matrix we show that Cx43 inhibition disrupts calcium oscillations in cultured fibroblasts and that this inhibits collective migration of fascia EPFs necessary to mobilize fascia matrix into open wounds. Cell–cell communication through Cx43 thus mediates matrix movement and scar formation, and is necessary for patch repair of voluminous wounds. These mechanistic findings have broad clinical implications toward treating fibrosis, aggravated scarring and impaired wound healing.
ISSN:0945-053X
1569-1802
DOI:10.1016/j.matbio.2021.01.005