Search

The lack of immune cells in mid-gestational fetal skin is often mentioned as a key factor underlying scarless healing. However, the scarless healing ability is conserved until long after the immune system in the fetus is fully developed. Therefore, we studied human second-trimester fetal skin and compared the numbers of immune cells and chemokine levels from fetal skin with adult skin. By using immunohistochemistry, we show that healthy fetal skin contains significant lower numbers of CD68(+) -macrophages, Tryptase(+) -mast cells, Langerin(+) -Langerhans cells, CD1a(+) -dendritic cells, and CD3(+) -T cells compared to adult skin. Staining with an early lineage leukocyte marker, i.e., CD45, verified that the number of CD45(+) -immune cells was indeed significantly lower in fetal skin but that sufficient numbers of immune cells were present in the fetal lymph node. No differences in the vascular network were observed between fetal and adult skin. Moreover, significant lower levels of lymphocyte chemokines CCL17, CCL21, and CCL27 were observed in fetal skin. However, levels of inflammatory interleukins such as IL-6, IL-8, and IL-10 were undetectable and levels of CCL2 were similar in healthy fetal and adult skin. In conclusion, this study shows that second-trimester fetal skin contains low levels of immune cells and leukocyte chemokines compared to adult skin. This immune cell deficiency includes CD45(+) leukocytes, despite the abundant presence of these cells in the lymph node. The immune deficiency in healthy second-trimester fetal skin may result in reduced inflammation during wound healing, and could underlie the scarless healing capacities of the fetal skin.

Scarless wound healing is a unique and intrinsic capacity of the fetal skin that is not fully understood. Further insight into the underlying mechanisms of fetal wound healing may lead to new therapeutic approaches promoting adult scarless wound healing. Differences between fetal and adult wound healing are found in the extracellular matrix, the inflammatory reaction and the levels of growth factors present in the wound. This review focuses specifically on transforming growth factor β (TGF-β), as this growth factor is prominently involved in wound healing and fibroblast-to-myofibroblast differentiation. Although fetal fibroblasts do respond to TGF-β, they lack a proliferative and a contractile response and display short-lived myofibroblast differentiation, autocrine response, and collagen up-regulation in comparison with adult fibroblasts. Curiously, prolonged TGF-β activation is associated with fibrosis, and therefore, this short-lived response in fetal fibroblasts might contribute to scarless healing. This review gives an overview of the current knowledge on TGF-β signaling and the intracellular TGF-β signaling pathway in fetal fibroblasts. Furthermore, this review also describes the various components that regulate the cellular TGF-β response and hypothesizes about the possible roles these components might play in the altered response of fetal fibroblasts to TGF-β. © 2013 by the Wound Healing Society.

Transforming growth factor-β (TGF-β) is a cytokine occurring in three isoforms with an important function in development and wound healing. In wound healing, prolonged TGF-β signaling results in myofibroblast differentiation and fibrosis. In contrast, the developing second-trimester fetal skin contains high levels of all three TGF-β isoforms but still has the intrinsic capacity to heal without scarring. Insight into TGF-β signal transduction during fetal wound healing might lead to methods to control the signaling pathway during adult wound healing. In this study, we imitated wound healing in vitro by stimulating fibroblasts with TGF-β1 and examining myofibroblast differentiation. The aim was to gain insight into TGF-β signaling in human fibroblasts from fetal and adult dermis. First, TGF-β1 stimulation resulted in similar or even more severe upregulation of myofibroblast-associated genes in fetal fibroblasts compared to adult fibroblasts. Second, fetal fibroblasts also had higher protein levels of myofibroblast-marker α-smooth muscle actin (α-SMA). Third, stimulated fetal fibroblasts in collagen matrices had higher protein levels of α-SMA, produced more of the fibrotic protein fibronectin splice-variant extra domain A (FnEDA), and showed enhanced contraction. Finally, fetal fibroblasts also produced significant higher levels of TGF-β1. Altogether, these data show that in vitro cultured fetal fibroblasts have myofibroblast-associated characteristics and do produce a fibrotic environment. As healthy fetal skin has high levels of TGF-β1, FnEDA, and collagen-III as well, these findings correlate with the in vivo situation. Therefore, our study demonstrates that there are similarities between fetal skin development and fibrosis and shows the necessity to discriminate between these processes.

The lack of immune cells in mid-gestational fetal skin is often mentioned as a key factor underlying scarless healing. However, the scarless healing ability is conserved until long after the immune system in the fetus is fully developed. Therefore, we studied human second-trimester fetal skin and compared the numbers of immune cells and chemokine levels from fetal skin with adult skin. By using immunohistochemistry, we show that healthy fetal skin contains significant lower numbers of CD68(+) -macrophages, Tryptase(+) -mast cells, Langerin(+) -Langerhans cells, CD1a(+) -dendritic cells, and CD3(+) -T cells compared to adult skin. Staining with an early lineage leukocyte marker, i.e., CD45, verified that the number of CD45(+) -immune cells was indeed significantly lower in fetal skin but that sufficient numbers of immune cells were present in the fetal lymph node. No differences in the vascular network were observed between fetal and adult skin. Moreover, significant lower levels of lymphocyte chemokines CCL17, CCL21, and CCL27 were observed in fetal skin. However, levels of inflammatory interleukins such as IL-6, IL-8, and IL-10 were undetectable and levels of CCL2 were similar in healthy fetal and adult skin. In conclusion, this study shows that second-trimester fetal skin contains low levels of immune cells and leukocyte chemokines compared to adult skin. This immune cell deficiency includes CD45(+) leukocytes, despite the abundant presence of these cells in the lymph node. The immune deficiency in healthy second-trimester fetal skin may result in reduced inflammation during wound healing, and could underlie the scarless healing capacities of the fetal skin.

Background TGF-β plays an important role in growth and development but is also involved in scarring and fibrosis. Differences for this growth factor are known between scarless fetal wound healing and adult wound healing. Nonetheless, most of the data in this area are from animal studies or in vitro studies and, thus, information about the human situation is incomplete and scarce. Objective The aim of this study was to compare the canonical TGF-β signaling in unwounded human fetal and adult skin. Methods Q-PCR, immunohistochemistry, Western Blot and Luminex assays were used to determine gene expression, protein levels and protein localization of components of this pathway in healthy skin. Results All components of the canonical TGF-β pathway were present in unwounded fetal skin. Compared to adult skin, fetal skin had differential concentrations of the TGF-β isoforms, had high levels of phosphorylated receptor-Smads, especially in the epidermis, and had low expression of several fibrosis-associated target genes. Further, the results indicated that the processes of receptor endocytosis might also differ between fetal and adult skin. Conclusion This descriptive study showed that there are differences in gene expression, protein concentrations and protein localization for most components of the canonical TGF-β pathway between fetal and adult skin. The findings of this study can be a starting point for further research into the role of TGF-β signaling in scarless healing.

Scarless wound healing is a unique and intrinsic capacity of the fetal skin that is not fully understood. Further insight into the underlying mechanisms of fetal wound healing may lead to new therapeutic approaches promoting adult scarless wound healing. Differences between fetal and adult wound healing are found in the extracellular matrix, the inflammatory reaction and the levels of growth factors present in the wound. This review focuses specifically on transforming growth factor β (TGF-β), as this growth factor is prominently involved in wound healing and fibroblast-to-myofibroblast differentiation. Although fetal fibroblasts do respond to TGF-β, they lack a proliferative and a contractile response and display short-lived myofibroblast differentiation, autocrine response, and collagen up-regulation in comparison with adult fibroblasts. Curiously, prolonged TGF-β activation is associated with fibrosis, and therefore, this short-lived response in fetal fibroblasts might contribute to scarless healing. This review gives an overview of the current knowledge on TGF-β signaling and the intracellular TGF-β signaling pathway in fetal fibroblasts. Furthermore, this review also describes the various components that regulate the cellular TGF-β response and hypothesizes about the possible roles these components might play in the altered response of fetal fibroblasts to TGF-β.

Item does not contain fulltext PURPOSE: The ileal conduit has been considered the gold standard urinary diversion for patients with bladder cancer and pediatric patients. Complications are mainly related to the use of gastrointestinal tissue. Tissue engineering may be the technical platform on which to develop alternatives to gastrointestinal tissue. We developed a collagen-polymer conduit and evaluated its applicability for urinary diversion in pigs. MATERIALS AND METHODS: Tubular constructs 12 cm long and 15 mm in diameter were prepared from bovine type I collagen and Vypro(R) II synthetic polymer mesh. Characterized tubes were sterilized, seeded with and without primary porcine bladder urothelial cells, and implanted as an incontinent urostomy using the right ureter in 10 female Landrace pigs. At 1 month the newly formed tissue structure was functionally and microscopically evaluated by loopogram and immunohistochemistry, respectively. RESULTS: The survival rate was 80% with 1 related and 1 unrelated death. By 1 month the collagen was resorbed and a retroperitoneal tunnel had formed that withstood 40 cm H(2)O water pressure. In 5 cases the tunnel functioned as a urostomy. Histological analysis revealed a moderate immune response, neovascularization and urothelial cells in the construct lumen. The polymer mesh provoked fibroblast deposition and tissue contraction. No major differences were observed between cellular and acellular constructs. CONCLUSIONS: After implanting the tubular constructs a retroperitoneal tunnel was formed that functioned as a urinary conduit in most cases. Improved large tubular scaffolds may generate alternatives to gastrointestinal tissue for urinary diversion. 01 augustus 2012