Expression profile of proteins involved in scar formation in the healing process of full‐thickness excisional wounds in the porcine model

Abstract

Scar formation in deep dermal wounds is associated with excessive collagen deposition and contraction. Increased collagen synthesis and decreased collagen degradation are the mechanisms through which this form of fibrosis can occur. Another factor might be a different kind of collagen cross-linking seen in fibrotic skin diseases. This type of cross-linking is dependent on the enzyme lysyl hydroxylase-2b. In this study, we examined the expression profile of the potential key players in scar formation in time in healing of acute wounds. Collagen types I and III, lysyl hydroxylase-2b, alpha-smooth muscle actin, transforming growth factor betas, and the matrix metalloproteinases and their inhibitor mRNA levels were determined. All genes examined show distinct expression patterns over time. The expression of lysyl hydroxylase-2b peaks at day 7, and precedes collagen types I and III expression. Eight weeks after wounding, the scars showed an increased level of lysyl hydroxylase-2b-mediated collagen cross-linking. This study shows that the fibrosis-specific type of cross-linking of collagen seen in human hypertrophic scarring also plays a role in this animal model of wound healing. Moreover, the expression of the putative gene responsible for this type of cross-linking, the lysyl hydroxylase-2b, is elevated during wound healing.

Granulation tissue formation and remodeling

“…These findings complement findings from a rat skin granulation tissue model showing a gradual increase in stabilization of collagen fibrils with a peak at three weeks (178). In pig skin wounds, LH-2-dependent collagen crosslinks were elevated still eight weeks after wounding (269). Secreted transglutaminase appears first in granulation tissue at day 3 after wounding.…”

Genetic loci that regulate healing and regeneration in LG/J and SM/J mice

“…These include Bmp5 , which has been shown to be involved in chondrogenesis and muscle and bone development (Guenther et al, 2008; Reber-Muller et al, 2006), and is down regulated in LG/J, potentially inhibiting premature formation of cartilage and muscle. Also, Plod2 (procollagen lysine, 2-oxoglutarate 5-dioxygenase 2 or LH2) is a membrane-bound enzyme which hydrolyzes collagen allowing cross-linking and is important in the formation of scar tissue (Ulrich et al , 2007); this is down regulated in LG/J which could allow growth over scarring. Rbp-2 retinol (Vitamin A) binding protein (also known as crbp - 2 or crbpII ) is involved with cell cycle control and is down regulated in chick limb development (Maden et al, 1989; Roesch et al, 2006).…”

Altered TGF‐β signaling in fetal fibroblasts: What is known about the underlying mechanisms?

“…Notably, the TGF-β isoforms appear to have overlapping functions in vitro despite the differences in expression patterns in vivo. 50,58,59 Insight into this TGF-β signaling in scarless fetal wound healing may result in methods to manipulate this cascade and eventually develop TGF-β-based antifibrotic therapies.…”

“…However, attempts to use TGF‐β1 and TGF‐β2 inhibitors and intradermal TGF‐β3 administrations have not led to a licensed therapeutic so far, and thus further elucidation of the mechanisms behind the TGF‐β signaling cascade is necessary. Notably, the TGF‐β isoforms appear to have overlapping functions in vitro despite the differences in expression patterns in vivo . Insight into this TGF‐β signaling in scarless fetal wound healing may result in methods to manipulate this cascade and eventually develop TGF‐β‐based antifibrotic therapies.…”