Role of TGF-β in Skin Chronic Wounds: A Keratinocyte Perspective

Abstract

Chronic wounds are characterized for their incapacity to heal within an expected time frame. Potential mechanisms driving this impairment are poorly understood and current hypotheses point to the development of an unbalanced milieu of growth factor and cytokines. Among them, TGF-β is considered to promote the broadest spectrum of effects. Although it is known to contribute to healthy skin homeostasis, the highly context-dependent nature of TGF-β signaling restricts the understanding of its roles in healing and wound chronification. Historically, low TGF-β levels have been suggested as a pattern in chronic wounds. However, a revision of the available evidence in humans indicates that this could constitute a questionable argument. Thus, in chronic wounds, divergences regarding skin tissue compartments seem to be characterized by elevated TGF-β levels only in the epidermis. Understanding how this aspect affects keratinocyte activities and their capacity to re-epithelialize might offer an opportunity to gain comprehensive knowledge of the involvement of TGF-β in chronic wounds. In this review, we compile existing evidence on the roles played by TGF-β during skin wound healing, with special emphasis on keratinocyte responses. Current limitations and future perspectives of TGF-β research in chronic wounds are discussed.

Human Skin Keratinocytes on Sustained TGF-β Stimulation Reveal Partial EMT Features and Weaken Growth Arrest Responses

“…In acute wound healing, TGF-β1 is provided by the abundant release from platelets; later, on the aggregated contributions by endothelial cells, fibroblasts, and keratinocytes themselves [39]. Yet, the available evidence indicates that elevated TGF-β levels sustain over time in the epidermis of chronic wounds [21][22][23]25]. Interestingly, fibroblasts isolated from chronic wounds exhibit unresponsiveness to TGF-β1 [4].…”

Carbon Dots Induce Epithelial‐Mesenchymal Transition for Promoting Cutaneous Wound Healing via Activation of TGF‐β/p38/Snail Pathway

“…[5,11,18] However, because HaCaT cells could express a large number of cell adhesion molecules (i.e., Ecadherin) during the prolif eration, which could form the adherens junctions to bind cells with each other, HaCaT cells tend to aggregate and appear clumped in Figure 2c, which is well consistent with the result of the previous report. [53] But just because of the confinement of the adhesion molecules, it makes the morphological varia tion of the HaCaT cells treated by CDots less obvious. Thus, HaCaT cells should be first digested by trypsin and then seeded into culture flasks for the detailed investigations of the morpho logical variation and the confirmation of EMT process.…”

MicroRNA-200b/c-3p regulate epithelial plasticity and inhibit cutaneous wound healing by modulating TGF-β-mediated RAC1 signaling

“…It will be desirable to test whether dysregulation of TGF-β1 contributes to the sustained expression of miR-200c-3p in chronic wound. In line with this notion, TGF-β signaling is impaired in aged skin or chronic wound 38 , 51 , 52 . In addition, altered expression of a number of miRNAs has been found in chronic wounds such as diabetic or aged skin wounds 21 , 26 , 53 .…”

“…Upon wounding, basal keratinocytes at the wound edge undergo epithelial-mesenchymal-transition (EMT)-like switch to commence migration. TGF-β1 is a potent activator of EMT and mediates cell migration, partially through RAC1 signaling pathway 29 , 38 . To determine whether and how miR-200b/c-3p regulate TGF-β1-stimulated keratinocyte movements, we used TGF-β1 to treat HaCaT cells with or without forced expression of miR-200b/c-3p and studied the motility properties.…”