Journal Article

Fibroblast state switching orchestrates dermal maturation and wound healing

Pisco, Angela Oliveira, Philippeos, Christina, Dilão, Rui, Mobasseri, Seyedeh Atefeh, Watt, Fiona M, Sipilä, Kalle H, Hiratsuka, Toru, Belmonte, Julio M, Rognoni, Emanuel

2018

Overview

Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here, we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual‐tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing. To test this, we performed in vivo live imaging of dermal fibroblasts, which revealed that homeostatic tissue architecture is achieved without active cell migration. In contrast, both fibroblast proliferation and migration are key determinants of tissue repair following wounding. The results show that tissue‐scale coordination is driven by the interdependence of cell proliferation and ECM deposition, paving the way for identifying new therapeutic strategies to enhance skin regeneration. Synopsis In vivo live imaging of dermal fibroblasts combined with mathematical modeling shows that fibroblast behaviour switching between two distinct states—proliferating and depositing ECM—defines dermal architecture. These findings are relevant for identifying new therapeutic strategies for skin regeneration. Tissue‐scale coordination in murine dermis is driven by the interdependence of cell proliferation and ECM deposition. The tissue architecture is set by a negative feedback loop between ECM deposition/remodelling and proliferation. Fibroblast lineages lose segregation with age. Fibroblast migration is the critical discriminator between dermal development and wound healing. Graphical Abstract In vivo live imaging of dermal fibroblasts combined with mathematical modeling shows that fibroblast behaviour switching between two distinct states—proliferating and depositing ECM—defines dermal architecture. These findings are relevant for identifying new therapeutic strategies for skin regeneration.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Animals / Architecture / Cell adhesion & migration / Cell growth / Cell Lineage - genetics / Cell migration / Cell Movement - genetics / Cell proliferation / Cell Proliferation - genetics / Cells, Cultured / Computer simulation / Deposition / Dermis / Dermis - growth & development / Dermis - metabolism / dermis development / EMBO11 / EMBO33 / EMBO39 / Extracellular matrix / Extracellular Matrix - genetics / Feedback / Feedback loops / fibroblast states / Fibroblasts / Fibroblasts - cytology / Fibroblasts - metabolism / Humans / In vivo methods and tests / Mathematical analysis / mathematical modelling / Mathematical models / Matrix methods / Maturation / Mice / Negative feedback / Regeneration / Skin / Skin - growth & development / Skin - metabolism / Switching / tissue architecture / Wound healing / Wound Healing - genetics