Ontogeny of expression of transforming growth factor‐β and its receptors and their possible relationship with scarless healing in human fetal skin

Abstract

Fetal cutaneous wounds that occur in early gestation heal without scar formation. Although much work has been done to characterize the role of transforming growth factor-beta (TGF-beta) isoforms and their receptors in the wound healing process, their roles in scarless wound repair observed in early gestation and their functions in human fetal skin development, and structural and functional maintenance are still not well understood. In this study, we explore the expression and distribution characteristics of three TGF-beta isoforms and their receptors, TGF-betaRI (TBRI) and TGF-betaRII (TBRII), in fetal and postnatal skins to understand the relevance of these five proteins to skin development and elucidate the mechanism(s) underlying the phenotypic transition from scarless to scar-forming healing observed during fetal gestation. Fetal skin biopsies of human embryo were obtained from spontaneous abortions at different gestational ages from 13 to 32 weeks and postnatal skin specimens were collected from patients undergoing plastic surgery. Gene expression and positive immunohistochemical signals of TGF-beta(1), TGF-beta(2), TGF-beta(3), TBRI, and TBRII could all be detected in fetal and postnatal skins. In early gestation, gene expression of TGF-beta(1), TBRI, and TBRII was weaker and protein contents were less compared with postnatal skins (p < 0.05). In contrast, more TGF-beta(2) mRNA transcript was found in early gestation than in late gestation and in postnatal skins, whereas protein content of this growth factor increased during gestation. Lastly, mRNA transcript and protein contents of TGF-beta(3) were apparently higher in early gestation compared to postnatal skin (p < 0.05). In postnatal skin, granules containing the three TGF-beta isoforms were mainly distributed in the cytoplasm and extracellular matrix of epidermal cells, interfollicular keratinocytes, and some fibroblasts. TBRI and TBRII were chiefly located in the cellular membrane of epidermal keratinocytes and some fibroblasts. The endogenous three TGF-beta isoforms and their receptors may be involved in the development of embryonic skin and in the maintenance of cutaneous structure and function, and also in postnatal wound healing. The differential levels of TGF-beta isoforms may provide either a predominantly antiscarring or profibrotic signal upon wounding depending on the gestational period. Lower expression of their receptors in early gestational skins may be a reason for the reduced ability to perceive ligands, ultimately leading to scar-free healing.

Transforming growth factor-β (TGF-β) signaling in healthy human fetal skin: A descriptive study

“…In line with observations of Chen et al [8], strong IHC staining for TGF-β1 was observed in the adult epidermis and dermis while positive staining was mainly observed in the fetal epidermis and the staining in fetal dermis was weak. TGF-β3 staining was observed in both the epidermis and dermis in fetal and adult skin but the staining was weaker in adult skin.…”

“…In this study the differential gene expression for the TGF-β isoforms in fetal skin was confirmed with low mRNA expression for TGF-β1 and high expression for TGF-β2 and -β3 (table 2) [8,10,11]. In line with observations of Chen et al [8], strong IHC staining for TGF-β1 was observed in the adult epidermis and dermis while positive staining was mainly observed in the fetal epidermis and the staining in fetal dermis was weak.…”

“…In contrast to the extensive studies on the TGF-β isoforms in the fetal skin, only little information is available about the other components of the canonical TGF-β pathway such as the TGF-βRs or the intracellular Smads. In human skin, one group studied the expression of both TGF-β and the TGF-βRs [8].…”

Novel Genomic Effects of Glucocorticoids in Epidermal Keratinocytes

“…We found that GCs suppress the expression of TGF␤1 and -2 but do not affect TGF␤3. Scarless (fetal-like) wound healing is associated with a lack of TGF␤1 and -2 response during fetal wound healing, whereas TGF␤3 activity remains intact (53). Therefore, our results would indicate that GCs may contribute to the reduction of scar formation by suppressing the expression of TGF␤1 and TGF␤2 but not of TGF␤3.…”

The inflammatory stimulus of a natural latex biomembrane improves healing in mice

“…Collagen production can be stimulated by the expression of TGF-β1 (38,39). However, immunohistochemical staining for TGF-β1 showed a decrease in this cytokine on days 7 and 14 in the presence of NLB, whereas an increase was observed in the ePTFE and sham groups.…”