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Review
. 2020 Jan 17;21(2):617.
doi: 10.3390/ijms21020617.

Scars or Regeneration?-Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

Dongsheng Jiang  1 , Yuval Rinkevich  1
Affiliations
Review

Scars or Regeneration?-Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

Dongsheng Jiang et al. Int J Mol Sci. .

Abstract

Scarring and regeneration are two physiologically opposite endpoints to skin injuries, with mammals, including humans, typically healing wounds with fibrotic scars. We aim to provide an updated review on fibroblast heterogeneity as determinants of the scarring-regeneration continuum. We discuss fibroblast-centric mechanisms that dictate scarring-regeneration continua with a focus on intercellular and cell-matrix adhesion. Improved understanding of fibroblast lineage-specific mechanisms and how they determine scar severity will ultimately allow for the development of antiscarring therapies and the promotion of tissue regeneration.

Keywords: adhesion; fibroblasts; fibrosis; regeneration; scarring.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Signaling pathways involved in wound-induced hair follicle neogenesis (WIHN). Wnt/β-catenin signaling and downstream Shh signaling in keratinocytes activates WIHN. TNF released from macrophages, FGF9 released from γδ T cells, and double-strand RNA binding to TLR3 in keratinocytes induces WIHN. Wnt//β-catenin and TGFβ/Smad signaling in fibroblasts results in fibrosis. Activation of Shh or suppression of Wnt pathways in fibrosis is sufficient to redirect Wnt-active wound fibroblasts to WIHN.
Figure 2
Figure 2
Signaling pathways leading to scarring or regeneration. The outcome of skin wound healing is a balance of signaling pathways leading to scarring or regeneration. Upregulation of Cadherins, ICAM-1, or Connexins or overactivation of Hippo/YAP, integrin/FAK/Rho GTPase, c-JUN/PI3K/AKT, or Wnt/β-catenin signaling in fibroblasts leads to pathological scarring, such as scleroderma, hypertrophic scar, and keloids. Activation of Sonic Hedgehog (Shh) signaling in keratinocytes and wound fibroblasts, or activation of Wnt/β-catenin, SOX2/PITX1, or TLR3/IL-6/STAT3 in keratinocytes (but not in fibroblasts) promotes regeneration, as seen in wound-induced hair follicle regeneration, oral mucosa repair, and fetal scarless healing. (FB), only in fibroblasts; (KC), only in keratinocytes.
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