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. 2018 Nov 21;99(1):665–706. doi: 10.1152/physrev.00067.2017

FIGURE 6.

FIGURE 6.

Re-epithelialization and fibroblast-epidermal cell interactions during wound healing. A: in the uninjured skin, the epidermis is multi-layered with the lowermost basal layer attached to the basement membrane. This layer contains K14+/β1-integrin positive stem cells that divide and differentiate to form the keratinocytes of the spinal and granular layers. The uppermost layer is the stratum corneum that contains cornified and impermeable cells. The epidermis also contains appendages of which the hair follicle and sebaceous gland are of particular interest since they contain several stem cell subsets with high activity even during homeostasis. The base of the hair follicle and hair germ, which is adjacent to the dermal papilla, contains LRG5+/ Gli1+ stem cells. The mid-bulge contains CD34+/Sox9+/keratin 15+ stem cells, and the upper bulge contains LRIG1+ stem cells. Melanocyte stem cells (McScs) are also dispersed in the hair bulge and germ. There are also stem cells that reconstitute the sebaceous glands. B: following wounding, unipotent stem cells within the hair follicle move in a linear fashion and take on a multipotent differentiation potential to reconstitute various cell types of the epidermis. Fibroblasts in the dermal papilla can signal these stem cells in the hair follicle through the Wnt/β-catenin pathway. In return, the epidermal stem cells signal the fibroblasts, converting them to myofibroblasts, to help in wound contraction. A subset of myofibroblasts become adipocytes, and this switch has been found to reduce scar formation. Another subset of fibroblasts with expression of CD26/En1 preferentially deposit higher levels of ECM and are responsible for fibrosis. Interfollicular stem cells in the basement membrane of the epidermis also proliferate to generate keratinocytes that lose their cell-cell junctions and migrate into the wound forming the epithelial tongue. The proliferation and migration of differentiated keratinocytes and stem cells into the wound, together lead to re-epithelialization of the wound. The illustration is a simplified rendering based on current knowledge.