EFFECTIVE SCARLESS WOUND HEALING MOLECULAR MARKERS
А.S. Dranitsina, O.V. Taburets, K.O. Dvorshchenko, D.M. Grebinyk, T.V. Beregova, L.I. Ostapchenko
Educational and Scientific Center "Institute of Biology and Medicine" of Taras Shevchenko Kyiv National University
DOI: https://doi.org/10.15407/fz63.03.068
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Abstract
The adverse physiological and psychological effects of scars
are broad, and there are currently no reliable treatments to prevent scarring. In contrast to adult wounds, early gestation
fetal skin wounds repair rapidly and in the absence of
scar formation. This intrinsic ability of fetal skin 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. Despite extensive investigation, the
mechanisms and molecular pathways of wound healing still
need to be elucidated to achieve a complete understanding of
this remodeling system. For some time, it has been known
that significant differences exist among the extracellular
matrix, inflammatory response, cellular mediators, and gene
expression profiles of fetal and postnatal wounds. The aim of
this paper is to discuss the main molecular markers involved
in scarless skin wound healing, their respective mechanisms
of action as well as problems and perspectives of scarring
treatment.
Keywords:
fetal; adult skin; wound; molecular markers; healing; treatment.
References
- Penn JW, Grobbelaar AO, Rolfe KJ. The role of the TGF-β family in wound healing, burns and scarring: a review. Int J Burn Trauma. 2012; 2(1):18–28.
PubMed PubMedCentral
- Helmo F R, Machado J R, de Oliveira Guimarães C S, de Paula Antunes Teixeira V, dos Reis M A, Corrêa R R M. Fetal wound healing biomarkers. Disease Markers. 2013; 35(6):939–44.
CrossRef
PubMed PubMedCentral
- Pastar I, Stojadinovic O, Yin NC., Ramirez H, Nusbaum AG., Sawaya A, Patel SB., Khalid L, Isseroff RR, Tomic-Canic M. Epithelialization in Wound Healing: A Comprehensive Review. Adv in wound care. 2014; 3(7):445–64.
CrossRef
PubMed PubMedCentral
- Vereschaka VV. Physical, mechanical and chemical properties of the skin in healthy all ages and people with symptoms of senile flabbiness facial skin: clinical and morphological parallels research methodology. Dermatol and Venereol. 2008; 1 (39): 20–33. [Ukrainian].
- Vereshchaka VV. Etiology and pathogenesis of senile face and sagging skin its structural mechanisms of change in modern man Caucasoid type / VV Vereshchaka. Science opinion, 2008.–481 p. [Ukrainian].
- Barrett J.L, Michael TL, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2010; 126(4):1172–80.
CrossRef
PubMed PubMedCentral
- Ehrlich HP, Kelley SF. Hypertrophic Scar: An interruption in the remodelling of repair- a laser Doppler blood flow study. Plast Reconstr Surg. 1992; 90:993–8.
CrossRef
- Reish RG, Eriksson E. Scars: a review of emerging and currently available therapies. Plast Reconstr Surg. 2008; 122:1068–78.
CrossRef
PubMed
- Wang J, Dodd C, Shankowsky HA, Sctt PG, Tredget EE. Deep dermal fibroblasts contribute to hypertrophic scarring. Lab Invest. 2008; 88:1278–90.
CrossRef
PubMed
- Madden JW, Peacock EE. Studies on the biology of collagen during wound healing: Dynamic metabolism of scar collagen and remodeling of dermal wounds. Ann Surg. 1971; 174:511–20.
CrossRef
- Colwell AS, Phan TT, Kong W, et al. Hypertrophic scar fibroblasts have increased connective tissue growth factor expression after transforming growth factor-beta stimulation. Plast Reconstr Surg. 2005; 116:1387–90.
CrossRef
PubMed
- Wilgus TA, Bergdall VK, Tober KL, Hill KJ, Mitra S, Flavahan NA, Oberyszyn TM. The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing. Am J Pathol. 2004; 165(3):753–61.
CrossRef
- Matthew PC, Martins VLC, O'Toole EA. Metalloproteinases and Wound Healing. Adv in wound care. 2015; 4(4):225–34.
CrossRef
PubMed PubMedCentral
- Rowlatt U. Intrauterine healing in a 20-week human fetus. Virchows Arch. 1979; 381:353–36.
CrossRef
- Rendl M, Lewis L, Fuchs E. Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS Biol. 2005; 3:1910–24.
CrossRef
PubMed PubMedCentral
- Beanes SR, Dang C, Soo C, Lorenz HP. Ontogenetic transition in the fetal wound extracellular matrix correlates with scar formation. Wound Repair Regen. 2001; 9–151.
- Wagers AJ, Christensen JL, Weissman IL. Cell fate determination from stem cells. Gene Ther. 2002; 9:606–12.
CrossRef
PubMed
- Coolen NA, Schouten KC, Boekema BK, Middelkoop E, Ulrich MM. Wound healing in a fetal, adult, and scar tissue model: a comparative study.Wound Repair and Regen. 2010; 18(3):291–301.
CrossRef
PubMed
- Longaker MT, Whitby DJ, Ferguson MW, Lorenz HP, Harrison MR, Adzick NS. Adult skin wounds in the fetal environment heal with scar formation. Ann Surg. 1994; 219:65–72.
CrossRef
PubMed PubMedCentral
- Beanes SR, Hu FY, Soo C, Dang CM, Urata M, Ting K, Atkinson JB, Benhaim P, Hedrick MH, Lorenz HP. Confocal microscopic analysis of scarless repair in the fetal rat: Defining the transition. Plast Reconstr Surg. 2002; 109:160–70.
CrossRef
PubMed
- Kennedy CI, Diegelmann RF, Haynes JH, Yager DR. Proinflammatory cytokines differentially regulate hyaluronan synthase isoforms in fetal and adult fibroblasts. J Pediatr Surg. 2000; 35:874–879.
CrossRef
PubMed
- Mast BA, Diegelmann RF, Krummel TM, Cohen IK. Hyaluronic acid modulates proliferation, collagen and protein synthesis of cultured fetal fibroblasts. Matrix. 1993; 13:441–446.
CrossRef
- Lorenz HP, Soo C, Beanes SR. Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in scarless fetal wound healing. Surg Forum. 2001:397–401.
- Chen W, Fu X, Ge S, Sun T, Sheng Z. Differentialexpression of matrix metalloproteinases and tissue-derived inhibitors of metalloproteinase in fetal and adult skins. Int J Biochem and Cell Biology. 2007; 39(5):997–1005.
CrossRef
PubMed
- McCallion RL, Ferguson MWJ, Clark RAF. Fetal wound healing and the development of anti-scarring therapies for adult wound healing in The Molecular and Cellular Biology of Wound Repair. 2nd ed., Ed Clarke RAF. New York: Plenum Press; 1996–600 p.
- Cass DL, Bullard KM, Sylvester KG, Yang EY, Sheppard D, Herlyn M, Adzick NS. Epidermal integrin expression is upregulated rapidly in human fetal wound repair. J Pediatric Surgery. 1998; 33(2):312–6.
CrossRef
- Lin C-H, Waters JM, Powell BC, Arkell RM, Cowin AJ. Decreased expression of Flightless I, a gelsolin family member and developmental regulator, in early-gestation fetal wounds improves healing. Mammalian Genome. 2011; 22(5–6):341–52.
CrossRef
PubMed
- Namazi MR, Fallahzadeh MK, Schwartz RA. Strategies for prevention of scars: what can we learn from fetal skin? Int J Dermatol. 2011; 50(1):85–93.
CrossRef
PubMed
- Singer AF, Clark RAF. Cutaneous wound healing. N Engl J Med. 1999; 341:738–46.
CrossRef
PubMed
- Jennings RW, Adzick NS, Longaker MT, et al. Ontogeny of fetal sheep polymorphonuclear leukocyte phagocytosis. J Pediatr Surg. 1991; 26:853–5.
CrossRef
- Clark RAF. Wound Repair Overview and General Considerations. New York: Plenum Press; 1996–400 p.
- Lorenz HP, Adzick NS. Scarless skin wound repair in the fetus. West J Med. 1993; 159:350–5.
PubMed PubMedCentral
- Ellis IR, Schor SL. Differential effects of TGF-1beta on hyaluronan synthesis by fetal and adult skin fibroblasts: Implications for cell migration and wound healing. Exp Cell Res. 1996; 228:326–33.
CrossRef
PubMed
- Estes JM, Vandeberg J, Adzick NS, et al. Phenotypic and functional features of myofibroblasts in sheep fetal wounds. Differentiation. 1994; 56:173–81.
CrossRef
PubMed
- Wu KK: Cyclooxygenase 2 induction: molecular mechanism and pathophysiologic roles. J Lab Clin Med. 1996; 128:242–5.
CrossRef
- Li HS, Hebda PA, Kelly LA, Ehrlich GD, Whitcomb DC, Dohar JE: Up-regulation of prostaglandin EP4 receptor messenger RNA in fetal rabbit skin wound. Arch Otolaryngol Head Neck Surg. 2000; 126:1337–43.
CrossRef
- Liechty KW, Adzick NS, Crombleholme TM. Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair. Cytokine. 2000; 12:671–6.
CrossRef
PubMed
- Liechty KW, Kim HB, Adzick NS, Crombleholme TM. Fetal wound repair results in scar formation in interleukin-10 deficient mice in a syngeneic murine model of scarless fetal wound repair. J Pediatr Surg. 2000; 35:866–72.
CrossRef
PubMed
- Yoshimura A., Wakabayashi Yu, Mori T. Cellular and molecular basis for the regulation of inflammation by TGF-β. J Biochem. 2010; 147(6):781–92.
CrossRef
PubMed PubMedCentral
- Klass BR, Grobbelaar AO, Rolfe KJ. Transforming growth factor beta 1 signalling, wound healing and epiair: a multifunctional cytokine with clinical implications for wound repair, a delicate balance. Postgrad Med J. 2009; 85:9–14.
CrossRef
PubMed
- Shi-Wen X, Leask A, Abraham D. Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth factor Rev. 2008; 19:133–44.
CrossRef
PubMed
- Pan D, Zhe X, Jakkaraju S, Taylot GA, Schuger L. P311 induces a TGF-β-independent, nonfibrogenic myofibroblasts phenotype. J Clin Invest. 2002; 110:1349–58.
CrossRef
PubMed PubMedCentral
- Cowin AJ, Holmes TM, Brosnan P, Ferguson MW. Expression of TGF-beta and its receptors in murine fetal and adult dermal wounds. Eur J Dermatol. 2001; 11:424–31.
PubMed
- Soo C, Beanes SR, Hu FY, Zhang X, Dang C, Chang G, Wang Y, Nishimura I, Freymiller E, Longaker MT, Lorenz HP, Ting K: Ontogenetic transition in fetal wound transforming growth factor-beta regulation correlates with collagen organization. Am J Pathol. 2003, 163:2459–76.
CrossRef
- Schneider JC, Holvanahalli R, Helm P, Goldstein R, Kowalske K. Contractures in burn injury: defining the problem. J Burn Care Res. 2006; 27:508-14.
CrossRef
PubMed
- Shah M, Foreman DM, Ferguson MW. Neutralizing antibody to TGF-beta reduces cutaneous scarring in adult rodents. J Cell Sci. 1994; 107:1137–57.
PubMed
- Hsu M, Peled ZM, Chin GS, Liu W, Longaker MT. Ontogeny of expression of transforming growth factorbeta 1 (TGF-beta 1), TGF-beta 3, and TGF-beta receptors I and II in fetal rat fibroblasts and skin. Plast Reconstr Surg. 2001; 107:1787–94.
CrossRef
PubMed
- Ferguson MW, Duncan J, Bond J, Bush J, Durani P, So K, Taylor L, Chantrey J, Mason T, James G, Laverty H, Occleston NL, Sattar A, Ludlow A, O'Kane S. Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo controlled , phase I/II studies. Lancet. 2009; 373:1264–74.
CrossRef
- Pratsinis H, Giannouli CC, Zervolea I, Psarras S, Stathakos D, Kletsas D. Differential proliferative response of fetal and adult human skin fibroblasts to transforming growth factor-beta. Wound Repair and Regen. 2004; 12(3):374–83.
CrossRef
PubMed
- Wilgus TA, Bergdall VK, Dipietro LA, Oberyszyn TM. Hydrogen peroxide disrupts scarless fetal wound repair. Wound Repair and Regen. 2005; 13(5):513–19.
CrossRef
PubMed
- Chin GS, Kim WJ, Lee TY, Liu W, Saadeh PB, Lee S, Levinson H, Gittes GK, Longaker MT. Differential expression of receptor tyrosine kinases and Shc in fetal and adult rat fibroblasts: toward defining scarless versus scarring fibroblast phenotypes. Plast Reconstr Surg. 2000; 105(3):972–9.
CrossRef
PubMed
- Hashimoto A, Kurosaki M, Gotoh N, Shibuya M, Kurosaki T. Shc regulates epidermal growth factor-induced activation of the JNK signaling pathway. J Biol Chem. 1999; 274(29):20139–43.
CrossRef
PubMed
- Colwell AS, Longaker MT, Lorenz HP. Identification of differentially regulated genes in fetal wounds during regenerative repair. Wound Repair Regen. 2008; 16:450.
CrossRef
PubMed
- Cheng J, Yu H, Deng S, Shen G. MicroRNA profiling in mid- and late-gestational fetal skin: implication for scarless wound healing. The Tohoku J Exp. Med. 2010; 221(3):203–9.
CrossRef
PubMed
- Carter R, Sykes V, Lanning D. Scarless fetal mouse wound healing may initiate apoptosis through caspase 7 and cleavage of PARP. J Surg. Res. 2009; 156(1):74–9.
CrossRef
PubMed
- Wei YJ, Yan XQ, Ma L, Wu JG, Zhang H, Qin LP. Oleanolic acid inhibits hypertrophic scarring in the rabbit ear model. Clin Exp Dermatol. 2011;36: 528–33.
CrossRef
PubMed
- Pastar I, Stojadinovic O, Krzyzanowska A, Barrientos S, Stuelten C, Zimmerman K, Blumenberg M, Brem H, Tomic-Canic M. Attenuation of the transforming growth factor beta-signaling pathway in chronic venous ulcers. Mol Med. 2010; 16: 92–101.
CrossRef
PubMed PubMedCentral
- Zhang Y, McCormick L, Gilliam A. Latency associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus host disease, a model for human scleroderma. J Invest Dermatol. 2003; 121:713–19.
CrossRef
PubMed
- Marquez-Aquirre A, Sandoval-Rodriguz A, Gonzalez- Cuevas J, Bueno-Topete M, NavarroPartida J, Arellano- Olivera I, Lucano-Laneros S, Armendariz-Borunda J. Adenoviral delivery of dominant negative transforming growth factor beta type II receptor up-regulates transcriptional repressor SKI-like oncogene, decreases matrix metalloproteinase 2 in hepatic stellate cell and prevents liver fibrosis in rats. J Gene Med. 2009; 11207–19.
- Ahn JY, Park S, Yun YS, Song JY. Inhibition of type III TGF-β- receptor aggravates lung fibrotic response. Biomed Pharmacother. 2010; 64:472–76.
CrossRef
PubMed
- Ferguson MW, Duncan J, Bond J, Bush J, Durani P, So K, Taylor L, Chantrey J, Mason T, James G, Laverty H, Occleston NL, Sattar A, Ludlow A, O'Kane S. Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo controlled , phase I/II studies. Lancet. 2009; 373:1264–74.
CrossRef
- Ehrlich HP, Kelley SF. Hypertrophic Scar: An interruption in the remodelling of repair- a laser Doppler blood flow study. Plast Reconstr Surg. 1992; 90:993–8.
CrossRef
- Reish RG, Eriksson E. Scars: a review of emerging and currently available therapies. Plast Reconstr Surg. 2008; 122:1068–78.
CrossRef
PubMed
- Agar N, Young AR. Melanogenesis: a photoprotective response to DNA damage? Mutation Res. 2005; 571:121–32.
CrossRef
PubMed
- El-Obeid A, Al-Harbi S, Al-Jomah N, Hassib A. Herbal melanin modulates tumor necrosis factor (TNF-alfa), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) production. Phytomedicine. 2006; 13: 324–33.
CrossRef
PubMed
- Taburets OV, Morgaienko OO, Kondratiuk TO, Beregova TV, Ostapchenko LI. The Effect of «Melanin-Gel» on the Wound Healing. Res J Pharmaceut Biol and Chem Sci. 2016; 7(3):2031–8.
- Dranitsina AS, Taburets OV, Dvorshchenko KO, Grebinyk DM, Beregova TV, Ostapchenko LI. TGFB 1, PTGS 2 Genes Expression during Dynamics of Wound Healing and with the Treatment of Melanin. Res J Pharmaceut Biol and Chem Sci. 2017; 8(1):2014–2023.
- Gao Fu-Lei, Jin Rong, Zhang Lu, Zhang Yu-Guang. The contribution of melanocytes to pathological scar formation during wound healing. Int J Clin Exp Med. 2013; 6(7):609–13.
PubMed PubMedCentral
- Cui Y, Wang XL, Xue J, Liu JY, Xie ML. Chrysanthemum morifolium extract attenuates high-fat milk-induced fatty liver through peroxisome proliferator-activated receptor alpha-mediated. Nutr Res. 2014; 34(3):268–75.
CrossRef
PubMed
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