Abstract
Wound healing is essential to repair the skin after injury. In the epidermis, distinct stem cells (SCs) populations contribute to wound healing. However, how SCs balance proliferation, differentiation and migration to repair a wound remains poorly understood. Here, we show the cellular and molecular mechanisms that regulate wound healing in mouse tail epidermis. 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. Functional experiments show that SC proliferation, migration and differentiation can be uncoupled during wound healing. 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. These results have important implications for tissue regeneration, acute and chronic wound disorders.
Highlights
Wound healing is essential to repair the skin after injury
At day 2 (D2) and even more at D4 following wounding, we found that BrdU incorporation was increased by 5-fold in a zone spanning from 500 mm to 1.5 mm from the leading edge (LE), with 40% of basal cells entering into cycle during a period of 4 h (Fig. 1b)
In contrast to what has been proposed for oesophagus repair and the growth of human keratinocytes in vitro[55,56], our data show that Wound healing (WH) does not increase the self-renewal capacities of progenitors, but rather leads to their massive depletion as proliferation increases
Summary
Wound healing is essential to repair the skin after injury. In the epidermis, distinct stem cells (SCs) populations contribute to wound healing. Different epidermal SCs coming from the hair follicle (HF), isthmus, infundibulum and interfollicular epidermis (IFE) contribute to WH5–12 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. 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 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
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