Scars are more severe when the subcutaneous fascia beneath the dermis is injured upon surgical or traumatic wounding. Here, we present a detailed analysis of fascia cell mobilisation by using deep tissue intravital live imaging of acute surgical wounds, fibroblast lineage-specific transgenic mice, and skin-fascia explants (scar-like tissue in a dish – SCAD). We observe that injury triggers a swarming-like collective cell migration of fascia fibroblasts that progressively contracts the skin and form scars. Swarming is exclusive to fascia fibroblasts, and requires the upregulation of N-cadherin. Both swarming and N-cadherin expression are absent from fibroblasts in the upper skin layers and the oral mucosa, tissues that repair wounds with minimal scar. Impeding N-cadherin binding inhibits swarming and skin contraction, and leads to reduced scarring in SCADs and in animals. Fibroblast swarming and N-cadherin thus provide therapeutic avenues to curtail fascia mobilisation and pathological fibrotic responses across a range of medical settings.
The origins of wound myofibroblasts and scar tissue remains unclear, but it is assumed to involve conversion of adipocytes into myofibroblasts. Here, we directly explore the potential plasticity of adipocytes and fibroblasts after skin injury. Using genetic lineage tracing and live imaging in explants and in wounded animals, we observe that injury induces a transient migratory state in adipocytes with vastly distinct cell migration patterns and behaviours from fibroblasts. Furthermore, migratory adipocytes, do not contribute to scar formation and remain non-fibrogenic in vitro, in vivo and upon transplantation into wounds in animals. Using single-cell and bulk transcriptomics we confirm that wound adipocytes do not convert into fibrogenic myofibroblasts. In summary, the injury-induced migratory adipocytes remain lineage-restricted and do not converge or reprogram into a fibrosing phenotype. These findings broadly impact basic and translational strategies in the regenerative medicine field, including clinical interventions for wound repair, diabetes, and fibrotic pathologies.
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