Hypoxia drives the transition of human dermal fibroblasts to a myofibroblast-like phenotype via the TGF-β1/Smad3 pathway

Abstract

Keloids, partially considered as benign tumors, are characterized by the overgrowth of fibrosis beyond the boundaries of the wound and are regulated mainly by transforming growth factor (TGF)-β1, which induces the transition of fibroblasts to myofibroblasts. Hypoxia is an important driving force in the development of lung and liver fibrosis by activating hypoxia inducible factor-1α and stimulating epithelial-mesenchymal transition. However, it is unknown whether and hypoxia can influence human dermal scarring. The aim of this study was to investigate whether hypoxia drives the transition of dermal fibroblasts to myofibroblasts and to clarify the potential transduction mechanisms involved. First, we observed that keloids are a relatively hypoxic tissue. Second, we found that hypoxia drives the transition of normal dermal fibroblasts to a myofibroblast-like phenotype [high expression of α-smooth muscle actin (α-SMA) and collagen I and III]. Finally, hypoxia effectively facilitated the nuclear import of the Smad2 and Smad3 complex, while blockade with the Smad3 inhibitor, SIS3, significantly impaired the expression of hypoxia-induced fibrosis-related molecules. Taken together, to the best of our knowledge, this study demonstrates for the first time that hypoxia facilitates the transition of dermal fibroblasts to myofibroblasts through the activation of the TGF-β1/Smad3 signaling pathway and our findings may provide a potential target for the treatment of keloids.

Histopathology and immunohistochemical analysis of 5‐fluorouracil and triamcinolone treated keloids in double‐blinded randomized controlled trial

“…In rather striking fashion, we do not see any difference in the vasculature between the keloids that responded to therapy and the ones that did not. The core of the keloid is considered to be under hypoxia . We obtained biopsies from the active border of the keloid.…”

“…Thus, keloids are the result of abnormal proliferation of fibroblasts and excessive extracellular matrix (ECM) deposition . In addition to these features, it has been stated that keloids are a relatively hypoxic tissue and that hypoxia may drive the transition of normal dermal fibroblasts to a myofibroblast‐like phenotype . In turn, myofibroblasts are the cells responsible for fibrosis and scar formation in many fibrotic conditions.…”

Current concepts on how to optimise skin needling 2020: A personal experience

“…I postulate that open wounds are exposed to much higher concentrations of oxygen, which favours TGFB1 and TGFB2, whereas the much lower normal oxygen tensions of tissue in needled skin favour TGFB3. The more anoxic the skin, that is, the bluer the skin looks after skin needling, the better are the results, as anoxia enhances growth factors 22 and possibly the effects of TGFB3 and also IL10 23–25 …”

The Role of the Renin-Angiotensin System and Vitamin D in Keloid Disorder—A Review

“…Some studies indicate hypervascularity in KLs (31), whilst others report limited microvasculature involvement associated with luminal occlusion primarily attributed to endothelial cells (32), favoring the role of hypoxia in keloid pathogenesis (33). The predominant cell types within KLs are fibroblasts and myofibroblasts, which are responsible for collagen and ECM deposition and wound contraction, respectively (34,35). Through the regulation of the TGF-β1/Smad3 pathway , fibroblasts transition to a myofibroblast phenotype causing subsequent excessive extracellular matrix (ECM) deposition, forming a persistent pathologic scar (35,36).…”

“…The predominant cell types within KLs are fibroblasts and myofibroblasts, which are responsible for collagen and ECM deposition and wound contraction, respectively (34,35). Through the regulation of the TGF-β1/Smad3 pathway , fibroblasts transition to a myofibroblast phenotype causing subsequent excessive extracellular matrix (ECM) deposition, forming a persistent pathologic scar (35,36). However, the precise origin of these aberrant myofibroblasts remains unclear (29).…”