Learning from regeneration research organisms: The circuitous road to scar free wound healing

Abstract

The skin is the largest organ in the body and plays multiple essential roles ranging from regulating temperature, preventing infection and ultimately defining who we are physically. It is a highly dynamic organ that constantly replaces the outermost cells throughout life. However, when faced with a major injury, human skin cannot restore a significant lesion to its original functionality, instead a reparative scar is formed. In contrast to this, many other species have the unique ability to regenerate full thickness skin without formation of scar tissue. Here we review recent advances in the field that shed light on how the skin cells in regenerative species react to injury to prevent scar formation versus scar forming humans.

Keywords: Collagen; Regeneration; Scar; Skin.

Fig. 1

Schematic diagram of mature mammalian skin. Skin consists of several layers of keratinocytes (indicated on the right) that differentiate as cells proceed from the basal layer to the cornified layer. As keratinocytes move through these layers of skin, their morphology and gene expression profiles also change (indicated on the left). Basal keratinocytes are the least differentiated cells and will express, TP63, several integrins, Keratin 4 and Keratin 15. Once keratinocytes are in the spinous layer, expression of Notch, miR-203, Keratin 1 and Keratin 10 will occur. After keratinocytes proceed through the granular layer, marked by keratohyalin and lamellar granules, keratinocytes will extrude all organelles and become cornified skeletons that form a ridged keratin network to form a barrier.

Fig. 2

A summary comparison of skin injury response in mammals versus axolotls. (A). In mammalian wound healing, a fibrin clot is formed, and keratinocytes will proliferate and migrate under the clot. As keratinocyte migration is occurring, fibroblasts will enter into the wound bed and proliferate, and will start to express extracellular matrix (ECM) proteins such as collagen. Once there is a provisional matrix, keratinocytes can migrate over to close the wound. Some fibroblasts will differentiate into myofibroblasts and will contract the wound. Scar formation is the result of mammalian wound healing, marked by a thickened epidermis, as well as excessive and un-remodeled collagen deposition. (B). In axolotl wound healing, keratinocytes will migrate over the fibrin clot, closing the wound within 24 h. Once the wound is closed, the keratinocytes will proliferate, and create a wound epidermis. Fibroblasts will enter the wound bed, proliferate, and secrete ECM. Again, some of the fibroblasts will differentiate into myofibroblasts and contract the wound. The cells within the dermis will then continue to remodel the ECM that was deposited until regeneration has been achieved.