The molecular mechanism of hypertrophic scar

Abstract

Hypertrophic scar (HTS) is a dermal form of fibroproliferative disorder which often develops after thermal or traumatic injury to the deep regions of the skin and is characterized by excessive deposition and alterations in morphology of collagen and other extracellular matrix (ECM) proteins. HTS are cosmetically disfiguring and can cause functional problems that often recur despite surgical attempts to remove or improve the scars. In this review, the roles of various fibrotic and anti-fibrotic molecules are discussed in order to improve our understanding of the molecular mechanism of the pathogenesis of HTS. These molecules include growth factors, cytokines, ECM molecules, and proteolytic enzymes. By exploring the mechanisms of this form of dermal fibrosis, we seek to provide some insight into this form of dermal fibrosis that may allow clinicians to improve treatment and prevention in the future.

Fig. 1

Ten year old male with hypertrophic scar to the chest and flank 16 months following a burn injury

Fig. 2

Regeneration occurs in superficial wounds while scarring occurs in deeper wounds (From Kwan P, Hori K, Ding J, Tredget EE (2009) Scar and contracture: biological principles. Hand Clin 25(4):511–28; with permission)

Fig. 3

Creation of deep and superficial scratch wounds and histological analysis of resulted scars. a Jig used to create the scratch wound model. b Wound created on the anterior thigh. c Scratch wound 70 days post-wounding. d Deep and superficial wound scar. e Deep wound scar tissue stained with hematoxylin and eosin staining (H&E). f Superficial wound scar tissue stained with H&E. Double-headed arrows in E and F indicate average thickness of epithelium. Arrowheads point to cells. Black arrows point to blood vessels. White arrows point to collagen. DW, deep wound; SW, superficial wound; DWS, deep wound scar; SWS, superficial wound scar (From Honardoust D, Varkey M, Marcoux Y, Shankowsky HA, Tredget EE (2012) Reduced decorin, fibromodulin, and transforming growth factor-β3 in deep dermis leads to hypertrophic scarring. J Burn Care Res 33(2):218–27; with permission)

Fig. 4

The TGF-β1 Smad signaling pathway contributes to HTS. TGF-βRI is activated after TGF-β1 binds to TGF-βRII. R-SMADs are then phosphorylated by ALK1 and ALK 5, two isoforms of TGF-βRI. The activated R-SMADs bind with Smad 4 and then translocate into nucleus and act as transcription factors. I-SMADs antagonize the effects of the R-SMADs and Co-SMADs

Fig. 5

Hypothetical diagram of the role of Th1/Th2/Th3 cells in stimulating bone marrow stem cells to healing wounds. (From Armour A, Scott PG, Tredget EE (2007) Cellular and molecular pathology of HTS: basis for treatment. Wound Repair Regen 15:S6-17; with permission)