Scarless wound healing: Transitioning from fetal research to regenerative healing

Abstract

Since the discovery of scarless fetal skin wound healing, research in the field has expanded significantly with the hopes of advancing the finding to adult human patients. There are several differences between fetal and adult skin that have been exploited to facilitate scarless healing in adults including growth factors, cytokines, and extracellular matrix substitutes. However, no one therapy, pathway, or cell subtype is sufficient to support scarless wound healing in adult skin. More recently, products that contain or mimic fetal and adult uninjured dermis were introduced to the wound healing market with promising clinical outcomes. Through our review of the major experimental targets of fetal wound healing, we hope to encourage research in areas that may have a significant clinical impact. Additionally, we will investigate therapies currently in clinical use and evaluate whether they represent a legitimate advance in regenerative medicine or a vulnerary agent. WIREs Dev Biol 2018, 7:e309. doi: 10.1002/wdev.309 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Plant Development > Cell Growth and Differentiation Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells.

Keywords: fetal wound healing; fibrosis; regenerative medicine; scarless; scarring; wound healing.

FIGURE 1

Anatomy of human skin. The most superficial layer of the skin is the epidermis, followed by the dermis, and then hypodermis. Also depicted in this figure is a specialized skin structure: the hair follicle. Note the dermal papilla, germinal matrix, and bulge regions

FIGURE 2

Interaction of cellular and humoral factors in wound healing. Note the key role of the macrophage. FGF2 = basic fibroblast growth factor; EGF = epidermal growth factor; GAGs = glycosaminoglycans; H₂O₂ = hydrogen peroxide; IFNG = interferon-gamma; IGF = insulin-like growth factor; IL1 = interleukin-1; IL6 = interleukin-6; KGF = keratinocyte growth factor; O₂⁻ = superoxide; -OH = hydroxyl radical; PDGF = platelet-derived growth factor; PGE2 = prostaglandin E2; TGFB = transforming growth factor-beta; TNFA = tumor necrosis factor-alpha; VEGF = vascular endothelial growth factor (Reprinted with permission from Townsend Beauchamp, Evers, and Mattox (2017). Copyright 2017 Elsevier)

FIGURE 3

Features of reparative scar formation and scarless regeneration in wound healing. ECM = extracellular matrix, MMP = matrix metalloproteinase; TGFB = transforming growth factor beta; TIMP = tissue inhibitor of metalloproteinase (Reprinted with permission from Leavitt et al., 2016. Copyright Springer)

FIGURE 4

Biomimetic materials are engineered to create favorable stem cell niches for in vitro experimental stem cell biology studies and for clinical use in regenerative medicine applications. Because all stem cells are exquisitely sensitive to environmental cues, the bioengineering component of regenerative medicine will be crucial to modulate and control stem cell behavior to allow effective cell-based therapies to be used clinically (Reprinted with permission from Townsend et al., 2017. Copyright Elsevier)