New insights into vertebrate skin regeneration

Regeneration biology has experienced a renaissance as clinicians, scientists, and engineers have combined forces to drive the field of regenerative medicine. Studies investigating the mechanisms that regulate wound healing in adult mammals have led to a good understanding of the stereotypical processes that lead to scarring. Despite comparative studies of fetal wound healing in which no scar is produced, the fact remains that insights from this work have failed to produce therapies that can regenerate adult human skin. In this review, we analyze past and contemporary accounts of wound healing in a variety of vertebrates, namely, fish, amphibians, and mammals, in order to demonstrate how examples of skin regeneration in adult organisms can impact traditional wound-healing research. When considered together, these studies suggest that inflammation and reepithelialization are necessary events preceding both scarring and regeneration. However, the extent to which these processes may direct one outcome over another is likely weaker than currently accepted. In contrast, the extent to which newly deposited extracellular matrix in the wound bed can be remodeled into new skin, and the intrinsic ability of new epidermis to regenerate appendages, appears to underlie the divergence between scar-free healing and the persistence of a scar. We discuss several ideas that may offer areas of overlap between researchers using these different model organisms and which may be of benefit to the ultimate goal of scar-free human wound healing.