Transforming growth factor‐β and its effect on reepithelialization of partial‐thickness ear wounds in transgenic mice

Abstract

Transforming growth factor-beta (TGF-beta) is known to affect nearly every aspect of wound repair. Many of the effects have been extensively investigated; however, the primary effect of endogenously derived TGF-beta on wound reepithelialization is still not completely understood. To examine this, two types of wounds were made on a transgenic mouse over-expressing TGF-beta1. Full-thickness back wounds were made to compare the wound healing process in the presence of compensatory healing mechanisms. Superficial partial-thickness ear wounds involving only the epidermis were made to determine the effect of TGF-beta on reepithelialization. In the partial-thickness ear wounds, at later time points, the transgenic group had smaller epithelial gaps than the wild-type mice. A greater number of actively proliferating cells, as determined by bromodeoxyuridine incorporation, was also found in the transgenic mice at post-injury day 8. These results show that TGF-beta1 stimulates the rate of reepithelialization at later time points in partial-thickness wounds. However, in the full-thickness back wounds, the transgenic animals exhibited a slower reepithelialization rate at all time points and the number of bromodeoxyuridine-positive cells was fewer. Our findings would suggest that the overexpression of TGF-beta1 speeds the rate of wound closure in partial-thickness wounds by promoting keratinocyte migration. In full-thickness wounds, however, the overexpression of TGF-beta1 slows the rate of wound reepithelialization.

Re-epithelialization of cutaneous wounds in adult zebrafish combines mechanisms of wound closure in embryonic and adult mammals

“…4). Strikingly, these effects were most pronounced in partial thickness wounds, which in contrast to full-thickness wounds, retain a basal dermal layer as a potential substrate for efficient keratinocyte migration, consistent with previous reports suggesting that TGF-β overexpression in mouse accelerates closure of only partial-thickness wounds (Tredget et al, 2005). Together, this suggests that, as in mammals, reepithelialization of wounds of adult zebrafish involves integrindependent lamellipodial crawling of keratinocytes at the LE.…”

“…In light of the positive in vivo effect of TGF-β on keratinocyte migration in zebrafish wounds revealed here (Fig. 4), it is tempting to speculate that despite the accelerated wound closure in mutant mice, TGF-β also has a positive effect on keratinocyte migration in closing mouse wounds in vivo, which is, however, overridden by other inhibitory effects, for instance on keratinocyte proliferation (Sivamani et al, 2007;Tredget et al, 2005).…”

Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

“…Consistently, many previous in vivo studies have indicated that TGF-␤/Smad signaling suppresses wound re-epithelialization. The re-epithelialization of full thickness wounds is delayed in TGF-␤1, BMP6, or Smad2 overexpressing transgenic mice (10,(12)(13)(14), and accelerated in mice expressing a dominant-negative type II TGF-␤ receptor (8) or Smad3-null mice (9). In contrast, the results from the mice with deletion of TGF-␤1 or Smad4, and mice overexpressing activin A, suggest a positive role of TGF-␤/Smad signaling in re-epithelialization (5-7).…”

Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing

“…This mechanism emphasizes the potential role of TGF-b1 in hypertrophic scar (HSc) formation in full thickness wounds. 36 The role of TGF-b1 in the later stages of wound healing…”