Tissue-scale coordination of cellular behaviour promotes epidermal wound repair in live mice

Abstract

Tissue repair is fundamental to our survival as tissues are challenged by recurrent damage. During mammalian skin repair, cells respond by migrating and proliferating to close the wound. However, the coordination of cellular repair behaviors and their effects on homeostatic functions in a live mammal remains unclear. Here we capture the spatiotemporal dynamics of individual epithelial behaviors by imaging wound re-epithelialization in live mice. Differentiated cells migrate while the rate of differentiation changes depending on local rate of migration and tissue architecture. Cells depart from a highly proliferative zone by directionally dividing towards the wound while collectively migrating. This regional co-existence of proliferation and migration leads to local expansion and elongation of the repairing epithelium. Finally, proliferation functions to pattern and restrict the recruitment of undamaged cells. This study elucidates the interplay of cellular repair behaviors and consequent changes in homeostatic behaviors that support tissue-scale organization of wound re-epithelialization.

Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche

“…Immunofluorescence analyses of back skin and intravital videomicroscopy of ear skin shows that the process begins at ~12 hr post wounding with migration rates being highest (~1.6 µm/day) at the wound edge by day 3 (Aragona et al, 2017; Keyes et al, 2016; Park et al, 2017). By contrast, in a fashion similar to that seen in closure of the embryonic epidermis over the eyelid (Heller et al, 2014), the proliferative response occurs in the region behind and only partially overlapping with the migrating epidermal front (Park et al, 2017). Similar migration and proliferation kinetics occur in wounded tail skin, where activated EpdSCs undergo rapid asymmetric fate outcome, visible by lineage-traced streams of cells that span from the proliferative zone to the wound center (Aragona et al, 2017).…”

“…However, by inhibiting GSK3β, WNTs can also promote accumulation of the active (unphosphorylated) state of key microtubule-binding proteins which stabilize and polarize microtubules at the wound front to facilitate wound repair (Wu et al, 2011). Further solidifying the importance of the cytoskeleton in migration and wound repair is the participation of the small GTPase and actin regulator RAC (Park et al, 2017). Integrins α5β1 cluster at the leading edge of the keratinocyte, where they participate in polarizing cell shape and cytoskeletal movements needed for effective epithelial migration and fibronectin assembly (Aragona et al, 2017; Coles et al, 2006; Heller et al, 2014; Qiao et al, 2014).…”

Epigenetic control in skin development, homeostasis and injury repair

“…Injury‐induced skin regeneration is a multistep process that involves various cell types including epithelial, immune and dermal cells . Here, we described our current knowledge about the role of epigenetic modifications in injury repair in adult skin.…”

Induction of hair follicle neogenesis with cultured mouse dermal papilla cells in de novo regenerated skin tissues

“…They are responsible for hair growth and also house stem cells that give rise to all epidermal lineages (hair follicle, skin, and sebaceous gland; Horsley et al, ; Jaks, Kasper, & Toftgard, ; Morris et al, ; P. Rompolas & Greco, ; Snippert et al, ; Taylor, Lehrer, Jensen, Sun, & Lavker, ; Nowak, Polak, Pasolli, & Fuchs, ). In addition, hair follicle stem cells can migrate out to the epidermis and contribute to epidermal renewal and reepithelialization after wounding (Levy, Lindon, Zheng, Harfe, & Morgan, ; Ito et al, ; Park et al, ). Although hair follicle bulge stem cells are dispensable for the acute phase of wound reepithelialization (I. Driskell, Oeztuerk‐Winder, Humphreys, & Frye, ; Garcin, Ansell, Headon, Paus, & Hardman, ; P. Rompolas, Mesa, & Greco, ), their absence delays wound healing (Langton, Herrick, & Headon, ; Liang et al, ).…”