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Human fetal wound healing: a review of molecular and cellular aspects

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Abstract

The physiological answer to after birth skin lesions is scarring, which compromises the function and the aesthetics of the injured area. However, fetuses in early gestation (24 weeks or less) respond to this damage with skin regeneration. To explain this difference, several factors are considered, such as increased production of collagen III in fetal fibroblasts and increased presence of this collagen in the skins of these fetuses. Increased hyaluronic acid in fetal matrix correlates with greater capacity for migration of fibroblasts in scarless repair. The fact that myofibroblasts in the wound appear only after the fetal stage of pregnancy which forms scars can also be correlated. Additionally, there is an increase in the amount of adhesion molecules in repair without scarring, which would multiply cell adhesion and migration. Lower levels of bTGF1 in fetal wound are correlated with reduced amounts of collagen I and may be the result of higher relative expression of bTGF3, which downregulates bTGF1. Amniotic fluid itself might be a stimulating factor to human skin’s fibroblasts proliferation through cytokines such as bFGF and PDGF. A hypoxic environment in the fetal wound, associated with increased presence of Dot cells in blood, is also observed, and both facts can be related to a difference in the repair of the skin. Distinct gene expression guides those different responses and may also help to elucidate fetal skin regeneration. When the mechanisms responsible for the absence of scars in wounded fetuses are enlightened, it will be a significant mark in the studies of wound cicatrization and its therapeutic applications shall be extremely valuable.

Level of evidence: Not ratable.

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References

  1. Lo DD, Zimmermann AS, Nauta A, Longaker MT, Lorenz HP (2012) Scarless fetal skin wound healing update. Birth Defects Research Part C: Embryo Today: Reviews 96(3):237–247

    Article  CAS  Google Scholar 

  2. Coolen NA, Schouten KC, Middelkoop E, Ulrich MM (2010) Comparison between human fetal and adult skin. Arch Dermatol Res 302(1):47–55

    Article  PubMed  Google Scholar 

  3. Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH (2009) Larsen, Embriologia humana. Elsevier, Rio de Janeiro, p 184

    Google Scholar 

  4. Xue M, Jackson CJ (2015) Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care 4(3):119–136

    Article  Google Scholar 

  5. Hu MS, Januszyk M, Hong WX et al (2014) Gene expression in fetal murine keratinocytes and fibroblasts. J Surg Res 190(1):344–357

  6. Mast BA, Diegelmann RF, Krummel TM, Cohen IK (1992) Scarless wound healing in the mammalian fetus. Surg Gynecol Obstet 174(5):441–451

    CAS  PubMed  Google Scholar 

  7. Leung A, Crombleholme TM, Keswani SG (2012) Fetal wound healing: implications for minimal scar formation. Curr Opin Pediatr 24(3):371–378

  8. Larson BJ, Longaker MT, Lorenz HP (2010) Scarless fetal wound healing: a basic science review. Plast Reconstr Surg 126(4):1172–1180

  9. Reinke JM, Sorg H (2012) Wound repair and regeneration. Eur Surg Res 49:35–43

    Article  CAS  PubMed  Google Scholar 

  10. Helmo FR, Machado JR, Guimarães CSO, Teixeira VPA, dos Reis MA, Corrêa RRM (2013) Fetal wound healing biomarkers. Dis Markers 35(6):939–944

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mazzone L, Pontiggia L, Reichmann E, Ochsenbein-Kölble N, Moehrlen U, Meuli M (2014) Experimental tissue engineering of fetal skin. Pediatr Surg Int 30(12):1241–7

    Article  CAS  PubMed  Google Scholar 

  12. Rolfe KJ, Grobbelaar AO (2012) A review of fetal scarless healing. ISRN Dermatol 2012:698034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wulff BC, Parent AE, Meleski MA et al (2012) Mast cells contribute to scar formation during fetal wound healing. J Invest Dermatol 132:458–465

    Article  CAS  PubMed  Google Scholar 

  14. Yates CC, Hebda P, Wells A (2012) Skin wound healing and scarring: fetal wounds and regenerative restitution. Birth Defects Res C Embryo Today: Reviews 96:325–333

    Article  CAS  Google Scholar 

  15. Balaji S, King A, Marsh E et al (2015) The role of interleukin-10 and hyaluronan in murine fetal fibroblast function in vitro: implications for recapitulating fetal regenerative wound healing. PLoS ONE 10(5):e0124302

    Article  PubMed  PubMed Central  Google Scholar 

  16. Walraven M (2016) Cellular and molecular mechanisms involved in scarless wound healing in the fetal skin. Available in http://dare.ubvu.vu.nl/handle/1871/54143. Accessed 20 March 2016

  17. Namazi MR, Fallahzadeh MK, Schwartz RA (2011) Strategies for prevention of scars: what can we learn from fetal skin? Int J Dermatol 50(1):85–93

    Article  PubMed  Google Scholar 

  18. Fernandez-Godino R, Pierce EA, Garland DL (2016) Extracellular matrix alterations and deposit formation in AMD. Adv Exp Med Biol 854:53–58

  19. Bielefeld KA, Amini-Nik S, Alman BA (2013) Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 70(12):2059–2081

    Article  CAS  PubMed  Google Scholar 

  20. Atala A, Lanza R, Thomson JA, Nerem R (eds) (2010) Principles of regenerative medicine., Academic Press

    Google Scholar 

  21. Myers SR, Ghanem AM (2015) Wound healing and scar formation. In: Farhadieh RD, Bulstrode NW, Cugno S (eds) Plastic and reconstructive surgery: approaches and techniques. John Wiley & Sons, Ltd, Chichester, UK. doi:10.1002/9781118655412.ch1

  22. Farhadieh R, Bulstrode N, & Cugno S (Eds.). (2015). Plast Reconstr Surg: Approaches and Techniques. John Wiley & Sons

  23. Tang JB, Zhou YL, Wu YF, Liu PY, Wang XT (2016) Gene therapy strategies to improve strength and quality of flexor tendon healing. Expert Opin Biol Ther 16(3):291–301

  24. Leitinger B (2015) The DDR receptor family. In: Wheeler DL, Yarden Y (eds) Receptor tyrosine kinases: family and subfamilies. Springer International Publishing, Switzerland, p 79–106

  25. Begnaud S et al (2016) Mechanics of epithelial tissues during gap closure. Curr Opin Cell Biol 42: 52–62.

  26. Lenselink EA (2015) Role of fibronectin in normal wound healing. Int Wound J 12(3):313–316

    Article  PubMed  Google Scholar 

  27. Penn JW, Grobbelaar AO, Rolfe KJ (2012) The role of the TGF-β family in wound healing, burns and scarring: a review. Int J Burns Trauma 2(1):18–28

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Leduc C, Sobilo L, Toumi H, Mondon P, Lespessailles E, Ossant F et al (2016) TGF-beta-induced early gene-1 overexpression promotes oxidative stress protection and actin cytoskeleton rearrangement in human skin fibroblasts. Biochim Biophys Acta Gen Subj 1860(6):1071–1078

  29. Young AM, Somoza PR (2015) Secreción de TGF-beta3 por células madre mesenquimáticas y su aplicación en ingeniería de tejidos. Available in http://dspace2.conicyt.cl/handle/10533/92392. Accessed 20 March 2016

  30. Chuang J, Barnes C, Wong BJ (2016) Overview of facial plastic surgery and current developments. Surg J 2(01):e17–e28

  31. Yang QQ, Yang SS, Tan JL, Luo GX, He WF, Wu J (2015) Process of hypertrophic scar formation: expression of eukaryotic initiation factor 6. Chin Med J 128(20):2787

  32. T Pritchard M, M McCracken J (2015) Identifying novel targets for treatment of liver fibrosis: what can we learn from injured tissues which heal without a scar? Curr Drug Targets 16(12):1332–1346

  33. Lee YS, Wysocki A, Warburton D, Tuan TL (2012) Wound healing in development. Birth Defects Res Part C: Embryo Today: Reviews 96(3):213–222

    Article  CAS  Google Scholar 

  34. Decker CG, Wang Y, Paluck SJ et al (2016) Fibroblast growth factor 2 dimer with superagonist in vitro activity improves granulation tissue formation during wound healing. Biomaterials 81:157–168

    Article  CAS  PubMed  Google Scholar 

  35. Akita S, Akino K, Hirano A (2013) Basic fibroblast growth factor in scarless wound healing. Adv Wound Care 2(2):44–49

    Article  Google Scholar 

  36. Zheng J, Song F, Lu SL, Wang XQ (2014) Dynamic hypoxia in scar tissue during human hypertrophic scar progression. Dermatol Surg 40(5):511–518

  37. Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2(7):a006502

  38. Wong WJ, Richardson T, Seykora JT, Cotsarelis G, Simon MC (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Investig Dermatol 135(2):454–461

    Article  CAS  PubMed  Google Scholar 

  39. Kong W, Li S, Longaker MT, Lorenz HP (2008) Blood-derived small Dot cells reduce scar in wound healing. Exp cell res 314(7):1529–1539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kong W, Li S, Lorenz HP (2010) Germ plasm‐like Dot cells maintain their wound regenerative function after in vitro expansion. Clin Exp Pharmacol and Physiol 37(4):e136–e144

    Article  CAS  Google Scholar 

  41. Degen KE, Gourdie RG (2012) Embryonic wound healing: a primer for engineering novel therapies for tissue repair. Birth Defects Res Part C: Embryo Today: Reviews 96(3):258–270

    Article  CAS  Google Scholar 

  42. Hu MSM, Rennert RC, McArdle A, Chung MT, Walmsley GG, Longaker MT et al (2014) The role of stem cells during scarless skin wound healing. Adv wound care 3(4):304–314

    Article  Google Scholar 

  43. Sriram G, Bigliardi PL, Bigliardi-Qi M (2015) Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro. Eur J Cell Biol Suppl 94(11):483–512

    Article  CAS  Google Scholar 

  44. Klein JD, Turner CG, Steigman SA et al (2011) Amniotic mesenchymal stem cells enhance normal fetal wound healing. Stem Cells Dev 20:969–976

    Article  CAS  PubMed  Google Scholar 

  45. Matsuura-Hachiya Y, Nakai Y, Abe K, Nishiyama T, Arai KY (2015) Recovery of extracellular matrix components by enalapril maleate during the repair process of ultraviolet B-induced wrinkles in mouse skin. Biochemistry and Biophysics Reports 4:180–186

    Article  Google Scholar 

  46. Colwell A, Longaker M, Lorenz PH (2005) Fetal wound healing. In: Falabella AF, Kirsner RS (eds) Wound healing. Boca Raton: Taylor & Francis, p 9–16

  47. Nyman E (2015) Guided regeneration of the human skin: in vitro and in vivo studies, vol 1450., Linköping University Electronic Press

    Google Scholar 

  48. Sennett R, Rendl M (2015) A scar is born: origins of fibrotic skin tissue. Science 348(6232):284–285

    Article  CAS  PubMed  Google Scholar 

  49. Kachgal S, Mace KA, Boudreau NJ (2012) The dual roles of homeobox genes in vascularization and wound healing. Cell Adh Migr 6(6):457–470

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Author information

Authors and Affiliations

  1. LIM 04- Medical Investigation Laboratory 04, University of Sao Paulo, Hospital das Clínicas, Sao Paulo, Sao Paulo, Brazil

    Leticia Hitomi Yagi, Larissa Martins Watanuki, Cesar Isaac, Yeda Midori Nakamura & Pedro Ribeiro Soares Ladeira

  2. Department of Surgery, Plastic Surgery Division, FMUSP, Sao Paulo, Brazil

    Rolf Gemperli

Authors
  1. Leticia Hitomi Yagi
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  2. Larissa Martins Watanuki
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  3. Cesar Isaac
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  4. Rolf Gemperli
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  5. Yeda Midori Nakamura
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  6. Pedro Ribeiro Soares Ladeira
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Correspondence to Leticia Hitomi Yagi.

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Conflict of interest

Leticia Hitomi Yagi, Larissa Martins Watanuki, Cesar Isaac, Rolf Gemperli, Yeda Midori Nakamura and Pedro Ribeiro Soares Ladeira, declare that they have no conflict of interest.

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For this type of study, a formal consent from a local ethics committee is not required. This article does not contain any studies with human participants or animals performed by any of the authors.

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Yagi, L.H., Watanuki, L.M., Isaac, C. et al. Human fetal wound healing: a review of molecular and cellular aspects. Eur J Plast Surg 39, 239–246 (2016). https://doi.org/10.1007/s00238-016-1201-y

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  • DOI: https://doi.org/10.1007/s00238-016-1201-y

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