![]() Immediately after wounding, there was no increase in BrdU incorporation. To define the role of cell proliferation during the regenerative stage of WH, we performed a 3 mm punch biopsy in the tail skin of adult mice and analysed the result of short-term BrdU incorporation by confocal microscopy on whole-mount epidermis at different time points during WH ( Fig. Spatiotemporal proliferation and migration during WH This clonal dynamic is very similar for different populations of epidermal SCs coming from different skin regions, suggesting that this cellular behaviour helps to maximize the regenerative process. As SCs become activated, they undergo rapid asymmetric cell fate outcome generating new SCs and progenitors that promote tissue expansion, visible as streaks of cells spanning from the proliferative hub to the centre of the wound. We show that at the beginning of WH, because of the incapacity of progenitors to switch from homoeostatic (asymmetric cell fate outcome at the population level) to a proliferative (symmetric renewal) mode of division, the important increase in cell proliferation leads to minimal tissue regeneration with a massive loss of progenitors through differentiation. To understand the mode of division and the cellular hierarchy of different populations of epidermal cells, we perform a detailed quantitative clonal analysis and mathematical modelling of the individual behaviour IFE and infundibulum cells during WH. We uncover the molecular signatures associated with these two distinct epidermal compartments and demonstrate that proliferation, migration and differentiation can be uncoupled during the early stage of wound repair. ![]() We define the spatiotemporal dynamics of these two compartments over the re-epithelialization stage. Here, using whole-mount tail epidermis, we identify and characterize molecularly and functionally two spatially distinct epithelial compartments surrounding the wound: a proliferative hub and a migrating leading edge (LE). It also remains unclear whether these cells simply increase their proliferation rate, maintaining a homoeostatic mode of division, or whether they switch to a proliferative mode of division leading to more symmetrical cell duplication to facilitate the expansion of newly formed skin. However, it remains unclear how different SCs populations can balance proliferation, differentiation and migration during the healing process, and whether they conform to the same proliferative dynamics. Different epidermal SCs coming from the hair follicle (HF), isthmus, infundibulum and interfollicular epidermis (IFE) contribute to WH 5, 6, 7, 8, 9, 10, 11, 12. Finally, the last stage, which can last for months, involves the remodelling of the epidermis, dermis and extracellular matrix (ECM). The second stage is the regenerative phase associated with re-epithelialization of the wound, the creation of new epidermal cells and the formation of the granulation tissue. Wound healing (WH) is organized in three stages 1, 2, 3, 4: the inflammation stage starts immediately, and is associated with the formation of the blood clot and the recruitment of inflammatory cells. Defects in these events can lead to improper repair causing acute and chronic wound disorders 2. When the skin barrier is disrupted, a cascade of cellular and molecular events is activated to repair the damage and restore skin integrity. The skin epidermis is a stratified epithelium that acts as a barrier protecting the animals against infections, trauma and water loss 1. These results have important implications for tissue regeneration, acute and chronic wound disorders. Lineage tracing and quantitative clonal analysis reveal that, following wounding, progenitors divide more rapidly, but conserve their homoeostatic mode of division, leading to their rapid depletion, whereas SCs become active, giving rise to new progenitors that expand and repair the wound. Functional experiments show that SC proliferation, migration and differentiation can be uncoupled during wound healing. Using a combination of proliferation kinetics experiments and molecular profiling, we identify the gene signatures associated with proliferation, differentiation and migration in different regions surrounding the wound. Here, we show the cellular and molecular mechanisms that regulate wound healing in mouse tail epidermis. However, how SCs balance proliferation, differentiation and migration to repair a wound remains poorly understood. ![]() ![]() In the epidermis, distinct stem cells (SCs) populations contribute to wound healing. Wound healing is essential to repair the skin after injury.
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