Fetal skin has the intrinsic capacity for wound healing, which is not correlated with the intrauterine environment. This intrinsic ability requires biochemical signals, which start at the cellular level and lead to secretion of transforming factors and expression of receptors, and specific markers that promote wound healing without scar formation. The mechanisms and molecular pathways of wound healing still need to be elucidated to achieve a complete understanding of this remodeling system. The aim of this paper is to discuss the main biomarkers involved in fetal skin wound healing as well as their respective mechanisms of action. 1. The Human Skin The skin is the largest organ of the human body and is responsible for the maintenance of homeostasis, hemodynamic control, sensory reception, and innate and adaptive immunity. The skin is divided into two layers: the epidermis and the dermis. The epidermis originates from the ectoderm and it is formed by different cell types. The dermis is derived from the mesoderm and is rich in dense connective tissues [1]. During embryonic development, the epidermis changes from a single layer of ectodermal cells at 7-8 days of gestation into a stratified, keratinized epithelium at 22–24 weeks of pregnancy [2]. Formation of hair follicles starts in the eighth week, and in the 12th week, the development of embryonic fibroblasts is organized in networks of collagen fibers [3, 4]. Type I collagen is the main component of the extracellular matrix (ECM) [5, 6] and it confers tensile strength [6]. Type I and type III collagen fibers are present in the fetal skin, and dermal fibroblast populations exhibit greater type I collagen compared to type III collagen staining [5]. Subsequently, the production of elastin by human skin fibroblasts increased from 7-fold to 14-fold between 17 and 19 weeks of pregnancy, reaching the levels found in neonatal skin fibroblasts [7]. The elastic tissue contributes to the structure of the fetal dermis and increases in quantity and complexity during intrauterine development [7]. With the advancement of the pregnancy, the number of epidermal cell layers increases and the hair follicles and sweat glands complete their maturation [8]. Fetal skin development is completed 30 weeks after conception [3, 9]. The complex maturation of human skin during fetal development is achieved by the action of chemical mediators. The organization and function of this organ may be compromised by numerous diseases or secondary mechanisms that lead to the loss of tissue continuity. The knowledge and understanding of the
References
[1]
L. R. Souto, J. Rehder, J. Vassallo, M. L. Cintra, M. H. Kraemer, and M. B. Puzzi, “Model for human skin reconstructed in vitro composed of associated dermis and epidermis,” Sao Paulo Medical Journal, vol. 124, no. 2, pp. 71–76, 2006.
[2]
N. A. Coolen, K. C. W. M. Schouten, E. Middelkoop, and M. M. W. Ulrich, “Comparison between human fetal and adult skin,” Archives of Dermatological Research, vol. 302, no. 1, pp. 47–55, 2010.
[3]
L. De Noronha, F. Medeiros, V. D. Martins et al., “Malformations of the central nervous system: analysis of 157 pediatric autopsics,” Arquivos de Neuro-Psiquiatria, vol. 58, no. 3 B, pp. 890–896, 2000.
[4]
F. Serri, W. Montagna, and H. Mescon, “Studies of the skin of the fetus and the child. II. glycogen and amylophos-phorylase in the skin of the fetus,” The Journal of Investigative Dermatology, vol. 39, pp. 199–217, 1962.
[5]
H. E. Brink, S. S. Stalling, and S. B. Nicoll, “Influence of serum on adult and fetal dermal fibroblast migration, adhesion, and collagen expression,” In Vitro Cellular and Developmental Biology—Animal, vol. 41, no. 8-9, pp. 252–257, 2005.
[6]
L. Cuttle, M. Nataatmadja, J. F. Fraser, M. Kempf, R. M. Kimble, and M. T. Hayes, “Collagen in the scarless fetal skin wound: detection with picrosirius-polarization,” Wound Repair and Regeneration, vol. 13, no. 2, pp. 198–204, 2005.
[7]
G. C. Sephel, A. Buckley, and J. M. Davidson, “Developmental initiation of elastin gene expression by human fetal skin fibroblasts,” Journal of Investigative Dermatology, vol. 88, no. 6, pp. 732–735, 1987.
[8]
N. A. Coolen, K. C. Schouten, B. K. Boekema, E. Middelkoop, and M. M. Ulrich, “Wound healing in a fetal, adult, and scar tissue model: a comparative study,” Wound Repair and Regeneration, vol. 18, no. 3, pp. 291–301, 2010.
[9]
J. Ersch and T. Stallmach, “Assessing gestational age from histology of fetal skin: an autopsy study of 379 fetuses,” Obstetrics and Gynecology, vol. 94, no. 5, pp. 753–757, 1999.
[10]
D. L. Cass, K. M. Bullard, K. G. Sylvester, E. Y. Yang, M. T. Longaker, and N. S. Adzick, “Wound size and gestational age modulate scar formation in fetal wound repair,” Journal of Pediatric Surgery, vol. 32, no. 3, pp. 411–415, 1997.
[11]
B. J. Larson, M. T. Longaker, and H. P. Lorenz, “Scarless fetal wound healing: a basic science review,” Plastic and Reconstructive Surgery, vol. 126, no. 4, pp. 1172–1180, 2010.
[12]
H. P. Lorenz, D. J. Whitby, M. T. Longaker, and N. S. Adzick, “Fetal wound healing: the ontogeny of scar formation in the non-human primate,” Annals of Surgery, vol. 217, no. 4, pp. 391–396, 1993.
[13]
C. Dang, K. Ting, C. Soo, M. T. Longaker, and H. P. Lorenz, “Fetal wound healing current perspectives,” Clinics in Plastic Surgery, vol. 30, no. 1, pp. 13–23, 2003.
[14]
J. R. Armstrong and M. W. Ferguson, “Ontogeny of the skin and the transition from scar-free to scarring phenotype during wound healing in the pouch young of a marsupial, Monodelphis domestica,” Developmental Biology, vol. 169, no. 1, pp. 242–260, 1995.
[15]
A. Leung, T. M. Crombleholme, and S. G. Keswani, “Fetal wound healing: implications for minimal scar formation,” Current Opinion in Pediatrics, vol. 24, no. 3, pp. 371–378, 2012.
[16]
T. A. Wilgus, V. K. Bergdall, K. L. Tober et al., “The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing,” American Journal of Pathology, vol. 165, no. 3, pp. 753–761, 2004.
[17]
T. A. Wilgus, V. K. Bergdall, L. A. Dipietro, and T. M. Oberyszyn, “Hydrogen peroxide disrupts scarless fetal wound repair,” Wound Repair and Regeneration, vol. 13, no. 5, pp. 513–519, 2005.
[18]
K. M. Bullard, D. L. Cass, M. J. Banda, and N. S. Adzick, “Transforming growth factor beta-1 decreases interstitial collagenase in healing human fetal skin,” Journal of Pediatric Surgery, vol. 32, no. 7, pp. 1023–1027, 1997.
[19]
W. Chen, X. Fu, S. Ge, T. Sun, and Z. Sheng, “Differential expression of matrix metalloproteinases and tissue-derived inhibitors of metalloproteinase in fetal and adult skins,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 5, pp. 997–1005, 2007.
[20]
A. S. Colwell, T. M. Krummel, M. T. Longaker, and H. P. Lorenz, “Wnt-4 expression is increased in fibroblasts after TGF-beta1 stimulation and during fetal and postnatal wound repair,” Plastic and Reconstructive Surgery, vol. 117, no. 7, pp. 2297–2301, 2006.
[21]
A. Parekh, V. C. Sandulache, A. S. Lieb, J. E. Dohar, and P. A. Hebda, “Differential regulation of free-floating collagen gel contraction by human fetal and adult dermal fibroblasts in response to prostaglandin E2 mediated by an EP2/cAMP-dependent mechanism,” Wound Repair and Regeneration, vol. 15, no. 3, pp. 390–398, 2007.
[22]
V. C. Sandulache, A. Parekh, H.-S. Li-Korotky, J. E. Dohar, and P. A. Hebda, “Prostaglandin E2 differentially modulates human fetal and adult dermal fibroblast migration and contraction: implication for wound healing,” Wound Repair and Regeneration, vol. 14, no. 5, pp. 633–643, 2006.
[23]
K. W. Liechty, N. S. Adzick, and T. M. Crombleholme, “Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair,” Cytokine, vol. 12, no. 6, pp. 671–676, 2000.
[24]
K. W. Liechty, T. M. Crombleholme, D. L. Cass, B. Martin, and N. S. Adzick, “Diminished interleukin-8 (IL-8) production in the fetal wound healing response,” Journal of Surgical Research, vol. 77, no. 1, pp. 80–84, 1998.
[25]
K. W. Liechty, H. B. Kim, N. S. Adzick, and T. M. Crombleholme, “Fetal wound repair results in scar formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair,” Journal of Pediatric Surgery, vol. 35, no. 6, pp. 866–873, 2000.
[26]
S. R. Goldberg, R. P. McKinstry, V. Sykes, and D. A. Lanning, “Rapid closure of midgestational excisional wounds in a fetal mouse model is associated with altered transforming growth factor-beta isoform and receptor expression,” Journal of Pediatric Surgery, vol. 42, no. 6, pp. 966–971, 2007.
[27]
C. Soo, S. R. Beanes, F.-Y. Hu et al., “Ontogenetic transition in fetal wound transforming growth factor-beta regulation correlates with collagen organization,” American Journal of Pathology, vol. 163, no. 6, pp. 2459–2476, 2003.
[28]
M. R. Namazi, M. K. Fallahzadeh, and R. A. Schwartz, “Strategies for prevention of scars: what can we learn from fetal skin?” International Journal of Dermatology, vol. 50, no. 1, pp. 85–93, 2011.
[29]
K. M. Sullivan, H. P. Lorenz, M. Meuli, R. Y. Lin, and N. S. Adzick, “A model of scarless human fetal wound repair is deficient in transforming growth factor beta,” Journal of Pediatric Surgery, vol. 30, no. 2, pp. 198–203, 1995.
[30]
A. S. Colwell, T. M. Krummel, M. T. Longaker, and H. P. Lorenz, “Fetal and adult fibroblasts have similar TGF-beta-mediated, smad-dependent signaling pathways,” Plastic and Reconstructive Surgery, vol. 117, no. 7, pp. 2277–2283, 2006.
[31]
H. Pratsinis, C. C. Giannouli, I. Zervolea, S. Psarras, D. Stathakos, and D. Kletsas, “Differential proliferative response of fetal and adult human skin fibroblasts to transforming growth factor-beta,” Wound Repair and Regeneration, vol. 12, no. 3, pp. 374–383, 2004.
[32]
G. S. Chin, W. J. Kim, T. Y. Lee et al., “Differential expression of receptor tyrosine kinases and Shc in fetal and adult rat fibroblasts: toward defining scarless versus scarring fibroblast phenotypes,” Plastic and Reconstructive Surgery, vol. 105, no. 3, pp. 972–979, 2000.
[33]
A. G. Batzer, D. Rotin, J. M. Urena, E. Y. Skolnik, and J. Schlessinger, “Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor,” Molecular and Cellular Biology, vol. 14, no. 8, pp. 5192–5201, 1994.
[34]
A. Hashimoto, M. Kurosaki, N. Gotoh, M. Shibuya, and T. Kurosaki, “Shc regulates epidermal growth factor-induced activation of the JNK signaling pathway,” Journal of Biological Chemistry, vol. 274, no. 29, pp. 20139–20143, 1999.
[35]
A. S. Colwell, M. T. Longaker, and H. P. Lorenz, “Identification of differentially regulated genes in fetal wounds during regenerative repair,” Wound Repair and Regeneration, vol. 16, no. 3, pp. 450–459, 2008.
[36]
J. Cheng, H. Yu, S. Deng, and G. Shen, “MicroRNA profiling in mid- and late-gestational fetal skin: implication for scarless wound healing,” The Tohoku Journal of Experimental Medicine, vol. 221, no. 3, pp. 203–209, 2010.
[37]
R. Carter, V. Sykes, and D. Lanning, “Scarless fetal mouse wound healing may initiate apoptosis through caspase 7 and cleavage of PARP,” Journal of Surgical Research, vol. 156, no. 1, pp. 74–79, 2009.
[38]
C.-H. Lin, J. M. Waters, B. C. Powell, R. M. Arkell, and A. J. Cowin, “Decreased expression of Flightless I, a gelsolin family member and developmental regulator, in early-gestation fetal wounds improves healing,” Mammalian Genome, vol. 22, no. 5-6, pp. 341–352, 2011.
[39]
I. R. Ellis and S. L. Schor, “Differential effects of TGF-beta1 on hyaluronan synthesis by fetal and adult skin fibroblasts: implications for cell migration and wound healing,” Experimental Cell Research, vol. 228, no. 2, pp. 326–333, 1996.
[40]
D. L. Cass, K. M. Bullard, K. G. Sylvester et al., “Epidermal integrin expression is upregulated rapidly in human fetal wound repair,” Journal of Pediatric Surgery, vol. 33, no. 2, pp. 312–316, 1998.
[41]
D. J. Whitby, M. T. Longaker, M. R. Harrison, N. S. Adzick, and M. W. Ferguson, “Rapid epithelialisation of fetal wounds is associated with the early deposition of tenascin,” Journal of Cell Science, vol. 99, no. 3, pp. 583–586, 1991.
[42]
K. M. Bullard, M. T. Longaker, and H. P. Lorenz, “Fetal wound healing: current biology,” World Journal of Surgery, vol. 27, no. 1, pp. 54–61, 2003.
[43]
M. T. Longaker, D. J. Whitby, N. S. Adzick, L. B. Kaban, and M. R. Harrison, “Fetal surgery for cleft lip: a plea for caution,” Plastic and Reconstructive Surgery, vol. 88, no. 6, pp. 1087–1092, 1991.
