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3D modeling of keloid scars in vitro by cell and tissue engineering

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Abstract

Keloids are pathologic scars defined as dermal fibrotic tumors resulting from a disturbance of skin wound healing process. Treatments against keloids are multiple, sometimes empirical and none of them really provides an effective tool for physicians. The lack of effective treatments is correlated with the poor understanding of keloid pathogenesis. To fill this gap, researchers need strong models mimicking keloids as closely as possible. The objective of this study was to establish in vitro a new reconstructed keloid model (RKM), by combining fibroblasts extracted from the three major area of a keloid (center, periphery, non-lesional) in a three-dimensional biomaterial. To this aim, fibroblasts of three keloid locations were extracted and characterized, and then integrated in a hydrated collagen gel matrix during a three-step procedure. The heterogeneity of fibroblasts was assessed according to their proliferative and remodeling capacities. RKMs were further visualized and characterized by both light and scanning electron microscopy. This reconstructed keloid model should be very useful for investigating keloid fibroblasts function in conditions mimicking in vivo situation. Moreover, RKM should also be a suitable model for either drug study and discovery or innovative approaches using medical devices both during cancer and cancer-like disease investigation.

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References

  1. Agha R, Ogawa R, Pietramaggiori G, Orgill DP (2011) A review of the role of mechanical forces in cutaneous wound healing. J Surg Res 171:700–708

    Article  PubMed  Google Scholar 

  2. Atiyeh BS, Costagliola M, Hayek SN (2005) Keloid or hypertrophic scar: the controversy: review of the literature. Ann Plast Surg 54:676–680

    Article  CAS  PubMed  Google Scholar 

  3. Bayat A, McGrouther DA, Ferguson MWJ (2003) Skin Scarring. BMJ 326:88–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bell E, Ivarsson B, Merrill C (1979) Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci 76:1274–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brown RA (2013) In the beginning there were soft collagen cell gels: towards better 3D connective tissue models? Exp Cell Res 319:2460–2469

    Article  CAS  PubMed  Google Scholar 

  6. Butler PD, Longaker MT, Yang GP (2008) Current progress in keloid research and treatment. J Am Coll Surg 206:731–741

    Article  PubMed  Google Scholar 

  7. Chike-Obi CJ, Cole PD, Brissett AE (2009) Keloids: pathogenesis, clinical features, and management. Semin Plast Surg 23:178–184

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chipev CC, Simman R, Hatch G, Katz AE, Siegel DM, Simon M (2000) Myofibroblast phenotype and apoptosis in keloid and palmar fibroblasts in vitro. Cell Death Differ 7:166–176

    Article  CAS  PubMed  Google Scholar 

  9. Ehrlich HP, Needle AL (1983) Wound healing in tight-skin mice: delayed closure of excised wounds. Plast Reconstr Surg 72:190–198

    Article  CAS  PubMed  Google Scholar 

  10. Ehrlich HP, Moyer KE (2013) Cell-populated collagen lattice contraction model for the investigation of fibroblast collagen interactions. Methods Mol Biol 1037:45–58

    Article  CAS  PubMed  Google Scholar 

  11. Hasegawa T, Nakao A, Sumiyoshi K, Tsuchihashi H, Ogawa H (2005) SB-431542 inhibits TGF-beta-induced contraction of collagen gel by normal and keloid fibroblasts. J Dermatol Sci 39:33–38

    Article  CAS  PubMed  Google Scholar 

  12. Jain P, Worthylake R, Alahari S (2012) Quantitative analysis of random migration of cells using time-lapse video microscopy. J Vis Exp 13:e3585

    Google Scholar 

  13. Janson DG, Saintigny G, van Adrichem A, Mahé C, El Ghalbzouri A (2012) Different gene expression patterns in human papillary and reticular fibroblasts. J Investig Dermatol 132:2565–2572

    Article  CAS  PubMed  Google Scholar 

  14. Janson D, Saintigny G, Mahé C, El Ghalbzouri A (2013) Papillary fibroblasts differentiate into reticular fibroblasts after prolonged in vitro culture. Exp Dermatol 22:48–53

    Article  CAS  PubMed  Google Scholar 

  15. Kamamoto F, Paggiaro AO, Rodas A, Herson MR, Mathor MB, Ferreira MC (2003) A wound contraction experimental model for studying keloids and wound-healing modulators. Artif Organs 27:701–705

    Article  PubMed  Google Scholar 

  16. Kischer CW, Pindur J, Shetlar MR, Shetlar CL (1989) Implants of hypertrophic scars and keloids into the nude (athymic) mouse: viability and morphology. J Trauma 29:672–677

    Article  CAS  PubMed  Google Scholar 

  17. Lee WJ, Choi I-K, Lee JH, Kim YO, Yun C-O (2013) A novel three-dimensional model system for keloid study: organotypic multicellular scar model. Wound Repair Regen 21:155–165

    Article  PubMed  Google Scholar 

  18. Li H, Nahas Z, Feng F, Elisseeff JH, Boahene K (2013) Tissue engineering for in vitro analysis of matrix metalloproteinases in the pathogenesis of keloid lesions. JAMA Facial Plast Surg 15:448–456

    Article  CAS  PubMed  Google Scholar 

  19. Ma H, Zhao X, Chen G, Fang R, Zhang F (2016) Silencing NLRC5 inhibits extracellular matrix expression in keloid fibroblasts via inhibition of transforming growth factor-β1/Smad signaling pathway. Biomed Pharmacother 83:1016–1021

    Article  CAS  PubMed  Google Scholar 

  20. Morris DE, Wu L, Zhao LL et al (1997) Acute and chronic animal models for excessive dermal scarring: quantitative studies. Plast Reconstr Surg 100:674–681

    Article  CAS  PubMed  Google Scholar 

  21. Phan TT, Lim IJ, Bay BH et al (2002) Differences in collagen production between normal and keloid-derived fibroblasts in serum-media co-culture with keloid-derived keratinocytes. J Dermatol Sci 29:26–34

    Article  CAS  PubMed  Google Scholar 

  22. Philandrianos C, Gonnelli D, Andrac-Meyer L, Bruno M, Magalon G, Mordon S (2014) Establishment of a keloid model by transplanting human keloid onto the backs of nude mice. Ann Chir Plast Esthet 59:246–252

    Article  CAS  PubMed  Google Scholar 

  23. Ridley A, Schwartz M, Burridge K et al (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709

    Article  CAS  PubMed  Google Scholar 

  24. Rolin G, Placet V, Jacquet E et al (2012) Development and characterization of a human dermal equivalent with physiological mechanical properties. Skin Res Technol 18:251–258

    Article  PubMed  Google Scholar 

  25. Saito M, Yamazaki M, Maeda T, Matsumura H, Setoguchi Y, Tsuboi R (2012) Pirfenidone suppresses keloid fibroblast-embedded collagen gel contraction. Arch Dermatol Res 304:217–222

    Article  CAS  PubMed  Google Scholar 

  26. Sarrazy V, Billet F, Micallef L, Coulomb B, Desmoulière A (2011) Mechanisms of pathological scarring: role of myofibroblasts and current developments. Wound Repair Regen 19(Suppl 1):s10–s15

    Article  PubMed  Google Scholar 

  27. Satish L, Lyons-Weiler J, Hebda PA, Wells A (2006) Gene expression patterns in isolated keloid fibroblasts. Wound Repair Regen 14:463–470

    Article  PubMed  Google Scholar 

  28. Sayah DN, Soo C, Shaw WW et al (1999) Downregulation of apoptosis-related genes in keloid tissues. J Surg Res 87:209–216

    Article  CAS  PubMed  Google Scholar 

  29. Seo BF, Lee JY, Jung SN (2013) Models of abnormal scarring. Bio Med Res Int 2013:423147

    Google Scholar 

  30. Shetlar MR, Shetlar CL, Kischer CW, Pindur J (1991) Implants of keloid and hypertrophic scars into the athymic nude mouse: changes in the glycosaminoglycans of the implants. Connect Tissue Res 26:23–36

    Article  CAS  PubMed  Google Scholar 

  31. Shih B, Garside E, McGrouther DA, Bayat A (2010) Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Repair Regen 18:139–153

    Article  PubMed  Google Scholar 

  32. Syed F, Ahmadi E, Iqbal SA, Singh S, McGrouther DA, Bayat A (2011) Fibroblasts from the growing margin of keloid scars produce higher levels of collagen I and III compared with intralesional and extralesional sites: clinical implications for lesional site-directed therapy. Br J Dermatol 164:83–96

    Article  CAS  PubMed  Google Scholar 

  33. Tucci-Viegas VM, Hochman B, França JP, Ferreira LM (2010) Keloid explant culture: a model for keloid fibroblasts isolation and cultivation based on the biological differences of its specific regions. Int Wound J 7:339–348

    Article  PubMed  Google Scholar 

  34. Tan EM, Hoffren J, Rouda S et al (1993) Decorin, versican, and biglycan gene expression by keloid and normal dermal fibroblasts: differential regulation by basic fibroblast growth factor. Exp Cell Res 209:200–207

    Article  CAS  PubMed  Google Scholar 

  35. Ud-Din S, Bayat A (2013) Strategic management of keloid disease in ethnic skin: a structured approach supported by the emerging literature. Br J Dermatol 169(Suppl 3):71–81

    Article  PubMed  Google Scholar 

  36. Uitto J, Perejda AJ, Abergel RP, Chu ML, Ramirez F (1985) Altered steady-state ratio of type I/III procollagen mRNAs correlates with selectively increased type I procollagen biosynthesis in cultured keloid fibroblasts. Proc Natl Acad Sci 82:5935–5939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Williams FN, Herndon DN, Branski LK (2014) Where we stand with human hypertrophic and keloid scar models. Exp Dermatol 23:811–812

    Article  PubMed  Google Scholar 

  38. Wu PH, Giri A, Wirtz D (2015) Statistical analysis of cell migration in 3D using the anisotropic persistent random walk model. Nat Protoc 10:517–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang J, Liu C, Wan Y, Peng L, Li W, Qiu J (2016) Long non-coding RNA H19 promotes the proliferation of fibroblasts in keloid scarring. Oncol Lett 12:2835–2839

    PubMed  PubMed Central  Google Scholar 

  40. Zhu KQ, Engrav LH, Gibran NS et al (2003) The female, red Duroc pig as an animal model of hypertrophic scarring and the potential role of the cones of skin. Burns 29:649–664

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Campus France, the French embassy in Thaïland and granted by PHC (Programme Hubert Curien) SIAM No. 31818 NK. Miss Suttho received a financial support from the national research university project under Thaïland’s Office of the Commission on Higher Education (CHE).

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Authors and Affiliations

  1. Laboratory of Physical Chemistry, Molecular and Cellular Biology, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Center of Excellence for Molecular Imaging, Chiang Mai University, Chiang Mai, Thailand

    Dutsadee Suttho & Samlee Mankhetkorn

  2. Clinical Investigation Center, Inserm CICB 1431, University Hospital of Besançon, 2 Place St Jacques, 25000, Besançon, France

    Dutsadee Suttho, Delphine Binda, Lionel Pazart, Philippe Humbert & Gwenaël Rolin

  3. Inserm UMR 1098, Engineering and Cutaneous Biology Team, Besançon, France

    Dutsadee Suttho, Philippe Humbert & Gwenaël Rolin

  4. University of Bourgogne Franche-Comté, SFR FED 4234, Besançon, France

    Dutsadee Suttho, Delphine Binda, Lionel Pazart, Philippe Humbert & Gwenaël Rolin

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  1. Dutsadee Suttho
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  2. Samlee Mankhetkorn
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  3. Delphine Binda
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  6. Gwenaël Rolin
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Correspondence to Gwenaël Rolin.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Suttho, D., Mankhetkorn, S., Binda, D. et al. 3D modeling of keloid scars in vitro by cell and tissue engineering. Arch Dermatol Res 309, 55–62 (2017). https://doi.org/10.1007/s00403-016-1703-2

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  • DOI: https://doi.org/10.1007/s00403-016-1703-2

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