Fibroblast state switching orchestrates dermal maturation and wound healing

SummaryMurine 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.Standfirst textWe show that fibroblast behaviour switching between two distinct states – proliferating and depositing ECM - is necessary and sufficient to define dermal architecture. Understanding this interdependence is critical for identifying new therapeutic strategies to enhance skin regeneration.HighlightsTissue-scale coordination in murine dermis is driven by the interdependence of cell proliferation and ECM depositionThe tissue architecture is set by a negative feedback loop between ECM deposition/remodelling and proliferationFibroblast lineages lose segregation with ageFibroblast migration is the critical discriminator between dermal development and wound healing</jats:sec

Loxl2 is dispensable for dermal development, homeostasis and tumour stroma formation

Medical Research Council (G1100073)Cancer Research UK (C219/A23522)Cancer Research UK (C219/A23522)Spanish Ministry of Economy and Innovation (SAF2016-76504-R)Instituto de Salud Carlos III (RTICC: RD12/0036/0007 and CIBERONC: CB16/12/00295)Worldwide Cancer Research (formerly AICR) (12-1057)EMBO long-term fellowship (aALTF594-2014)EMBO Advanced Fellowship (aALTF 523-2017