Scarless wound healing: finding the right cells and signals

Abstract

From the moment we are born, every injury to the skin has the potential to form a scar, many of which can impair form and/or function. As such, scar management constitutes a billion-dollar industry. However, effectively promoting scarless wound healing remains an elusive goal. The complex interactions of wound healing contribute to our inability to recapitulate scarless wound repair as it occurs in nature, such as in fetal skin and the oral mucosa. However, many new advances have occurred in recent years, some of which have translated scientific findings from bench to bedside. In vivo lineage tracing has helped establish a variety of novel cellular culprits that may act as key drivers of the fibrotic response. These newly characterized cell populations present further targets for therapeutic intervention, some of which have previously demonstrated promising results in animal models. Here, we discuss several recent studies that identify exciting approaches for diminishing scar formation. Particular attention will also be paid to the canonical Wnt/β-catenin signaling pathway, which plays an important role in both embryogenesis and tissue repair. New insights into the differential effects of Wnt signaling on heterogeneous fibroblast and keratinocyte populations within the skin further demonstrate methods by which wound healing can be re-directed to a more fetal scarless phenotype. Graphical abstract Recent approaches to reducing scar formation. Representation showing novel scientific approaches for decreasing scar formation, including the targeting of pro-fibrotic cell populations based on surface molecule expression (e.g. DPP4(+) fibroblasts, ADAM12(+) pericytes). Modulation of cellular mechanotransduction pathways are another means to reduce scar formation, both at the molecular level or, macroscopically with dressings designed to offload tension, at cutaneous wound sites (ADAM12 a disintegrin and metalloprotease 12, DPP4 dipeptidyl peptidase-4, FAK focal adhesion kinase).

Keywords: Fibroblast; Scarless; Wnt; Wound healing; β-catenin.

Figure 1. Recent approaches to reducing scar formation

Schematic showing novel scientific approaches for decreasing scar formation, including targeting pro-fibrotic cell populations based on surface molecule expression. Modulation of cellular mechanotransduction pathways are another means to reduce scar formation, both at the molecular level, or macroscopically with dressings designed to offload tension at cutaneous wound sites. ADAM12, a disintegrin and metalloprotease 12; DPP4, dipeptidyl peptidase-4; FAK, focal adhesion kinase.

Figure 2. Features of reparative scar formation and scarless regeneration in wound healing

ECM, extracellular matrix; MMP, matrix metalloproteinase; TGF-β, transforming growth factor beta; TIMP, tissue inhibitor of metalloproteinase.

Figure 3. Stem cell-based therapies to promote scarless wound healing

Schematic showing general principles of two cell-based therapeutic methodologies, (1) application of stem cell conditioned media and (2) direct application of stem cells to the wound bed. The poor survivability of mesenchymal stem cells (MSCs) transplanted to the wound bed has prompted development of other novel therapies that take advantage of the paracrine mechanisms of action of these cells. Application of conditioned media from umbilical cord blood-derived MSC (UCB-MSC) culture is one such example (Doi, et al., 2016).

Figure 4. Brief overview of canonical Wnt signaling and its associated targets

Wnt binding results in cytoplasmic accumulation of β-catenin, which is degraded in the absence of ligand binding. Subsequently, β-catenin translocates to the nucleus where it interacts with T cell-specific transcription factor/lymphoid enhancer-binding factor (Tcf/Lef) in order to modulate gene expression. CXXC5 (CXXC Finger Protein 5); Dkk-1, Dickkopf-1; LiCl, lithium chloride; TGF-β, transforming growth factor beta.