Fibroblast state switching orchestrates dermal maturation and wound healing.

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

doi:10.15252/msb.20178174

Emanuel Rognoni, Seyedeh Atefeh Mobasseri + Show 7 more

Open Access

https://doi.org/10.15252/msb.20178174

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Abstract

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.

Highlights

Mammalian skin comprises two mutually dependent layers, the epidermis and the dermis, which form through highly coordinated epithelial–mesenchymal interactions during development (Fuchs & Horsley, 2008; Watt, 2014)
During embryonic development, the dermis volume increased proportionally to the change in cell number, indicating that at this stage tissue growth is driven by cell proliferation. In line with this observation, we found that most fibroblasts are proliferating (Ki67+) at E10.5, but with age they progressively arrest in the G1 cell cycle phase, which we define as quiescence (Basak et al, 2017), without undergoing apoptosis (Rognoni et al, 2016; Figs 1B upper panel and C, and EV1B)
The second phase, corresponding to postnatal growth, is strongly associated with extracellular matrix (ECM) deposition and remodelling, as between postnatal day 2 (P2) and P50 the ratio of dermis volume to cell number is 4:1. These observations are supported by publicly available microarray data for neonatal and adult back skin fibroblasts, which show that with age there is a reduction in genes associated with proliferation, together with an enrichment for GO terms for ECM

Summary

Introduction

Mammalian skin comprises two mutually dependent layers, the epidermis and the dermis, which form through highly coordinated epithelial–mesenchymal interactions during development (Fuchs & Horsley, 2008; Watt, 2014). The dermis evolves from a multi-potent pool of Pdgfra+ fibroblasts These become lineage-restricted at embryonic day 16.5 (E16.5), such that. Lrig expressing fibroblasts give rise to the upper (papillary) dermis, while Sca1/Dlk1-positive fibroblasts give rise to the lower (reticular) dermis and hypodermis (Driskell et al, 2013). The papillary lineage is required for hair follicle formation in skin reconstitution assays, whereas the lower lineage gives rise to the fibroblasts that mediate the initial phase of wound repair (Driskell et al, 2013; Rognoni et al, 2016). By postnatal day 2 (P2), the hypodermis has formed, comprising differentiated adipocytes and preadipocytes, while fibroblasts from the upper dermis differentiate into the hair follicle arrector pili muscle. Resident immune cells, neuronal cells and endothelial cells are recruited, giving rise to the adult dermis

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