Reconstitution of Human Keloids in Mouse Skin

Overview

Journal Plast Reconstr Surg Glob Open

Specialty General Surgery

Date 2017 May 17

PMID 28507865

Citations 5

Authors

Ataru Sunaga

Hideaki Kamochi

Shunji Sarukawa

Hirokazu Uda

Yasushi Sugawara

Rintaro Asahi

Daekwan Chi

Shiho Nakagawa

Koji Kanayama

Kotaro Yoshimura

Affiliations

Soon will be listed here.

Abstract

Background: Keloids are a dermal fibroproliferative scar of unknown etiology. There is no good animal model for the study of keloids, which hinders the development and assessment of treatments for keloids.

Methods: Human keratinocytes and dermal fibroblasts were isolated from 3 human skin tissues: normal skin, white scars, and keloids. A mixed-cell slurry containing keratinocytes and dermal fibroblasts was poured into a double chamber implanted on the back of NOD/Shi-scid/IL-2Rγnull mice. After 12 weeks, the recipient mice had developed reconstituted human skin tissues on their backs. These were harvested for histological studies.

Results: Macroscopically, the reconstituted skins derived from both normal skin and white scars were similar to normal skin and white scars in humans, respectively. Keloid-derived reconstituted skins exhibited keloid-like hypertrophic nodules. Histological findings and immunohistochemical staining confirmed that the reconstituted skin tissues were of human origin and the keloid-derived reconstituted skin had the typical features of human keloids such as a hypertrophic dermal nodule, collagen type composition, orientation of collagen fibers, and versican expression.

Conclusion: The mouse model with humanized keloid tissue presented here should be a useful tool for future keloid research.

Citing Articles

Deciphering the single-cell transcriptome network in keloids with intra-lesional injection of triamcinolone acetonide combined with 5-fluorouracil.

Xia Y, Wang Y, Hao Y, Shan M, Liu H, Liang Z Front Immunol. 2023; 14:1106289.

PMID: 37275903 PMC: 10235510. DOI: 10.3389/fimmu.2023.1106289.

Human In Vitro Skin Models for Wound Healing and Wound Healing Disorders.

Hofmann E, Fink J, Pignet A, Schwarz A, Schellnegger M, Nischwitz S Biomedicines. 2023; 11(4).

PMID: 37189674 PMC: 10135654. DOI: 10.3390/biomedicines11041056.

Inhibition of growth of Asian keloid cells with human umbilical cord Wharton's jelly stem cell-conditioned medium.

Arjunan S, Gan S, Choolani M, Raj V, Lim J, Biswas A Stem Cell Res Ther. 2020; 11(1):78.

PMID: 32085797 PMC: 7035736. DOI: 10.1186/s13287-020-01609-7.

Animal Models for Studies of Keloid Scarring.

Supp D Adv Wound Care (New Rochelle). 2019; 8(2):77-89.

PMID: 31832272 PMC: 6906757. DOI: 10.1089/wound.2018.0828.

Inhibition as a Novel Therapeutic Target for Keloid Disease.

Park T, Kim C, Choi J, Park Y, Chong Y, Park M Adv Wound Care (New Rochelle). 2019; 8(5):186-194.

PMID: 31119062 PMC: 6529855. DOI: 10.1089/wound.2018.0910.

References

Hillmer M, MacLeod S . Experimental keloid scar models: a review of methodological issues. J Cutan Med Surg. 2002; 6(4):354-9. DOI: 10.1007/s10227-001-0121-y. View

LeBleu V, Taduri G, OConnell J, Teng Y, Cooke V, Woda C . Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013; 19(8):1047-53. PMC: 4067127. DOI: 10.1038/nm.3218. View

Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K . NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002; 100(9):3175-82. DOI: 10.1182/blood-2001-12-0207. View

Polo M, Kim Y, Kucukcelebi A, Hayward P, Ko F, ROBSON M . An in vivo model of human proliferative scar. J Surg Res. 1998; 74(2):187-95. DOI: 10.1006/jsre.1997.5251. View

Yagi Y, Muroga E, Naitoh M, Isogai Z, Matsui S, Ikehara S . An ex vivo model employing keloid-derived cell-seeded collagen sponges for therapy development. J Invest Dermatol. 2012; 133(2):386-93. DOI: 10.1038/jid.2012.314. View

Wang H, Luo S . Establishment of an animal model for human keloid scars using tissue engineering method. J Burn Care Res. 2012; 34(4):439-46. DOI: 10.1097/BCR.0b013e318269bd64. View

Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T . Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: retrospective study of 147 cases followed for more than 18 months. Plast Reconstr Surg. 2003; 111(2):547-53; discussion 554-5. DOI: 10.1097/01.PRS.0000040466.55214.35. View

Supp D, Hahn J, Glaser K, McFarland K, Boyce S . Deep and superficial keloid fibroblasts contribute differentially to tissue phenotype in a novel in vivo model of keloid scar. Plast Reconstr Surg. 2012; 129(6):1259-1271. DOI: 10.1097/PRS.0b013e31824ecaa9. View

Russell S, Russell J, Trupin K, Gayden A, Opalenik S, Nanney L . Epigenetically altered wound healing in keloid fibroblasts. J Invest Dermatol. 2010; 130(10):2489-96. PMC: 2939920. DOI: 10.1038/jid.2010.162. View

10.

Wang C, Nelson C, Brinkman A, Miller A, Hoeffler W . Spontaneous cell sorting of fibroblasts and keratinocytes creates an organotypic human skin equivalent. J Invest Dermatol. 2000; 114(4):674-80. DOI: 10.1046/j.1523-1747.2000.00938.x. View

11.

Washio H, Fukuda N, Matsuda H, Nagase H, Watanabe T, Matsumoto Y . Transcriptional inhibition of hypertrophic scars by a gene silencer, pyrrole-imidazole polyamide, targeting the TGF-β1 promoter. J Invest Dermatol. 2011; 131(10):1987-95. DOI: 10.1038/jid.2011.150. View

12.

SHETLAR M, SHETLAR C, Kischer C, Pindur J . Implants of keloid and hypertrophic scars into the athymic nude mouse: changes in the glycosaminoglycans of the implants. Connect Tissue Res. 1991; 26(1-2):23-36. DOI: 10.3109/03008209109152161. View

13.

Ishiko T, Naitoh M, Kubota H, Yamawaki S, Ikeda M, Yoshikawa K . Chondroitinase injection improves keloid pathology by reorganizing the extracellular matrix with regenerated elastic fibers. J Dermatol. 2013; 40(5):380-3. DOI: 10.1111/1346-8138.12116. View

14.

Aarabi S, Bhatt K, Shi Y, Paterno J, Chang E, Loh S . Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. FASEB J. 2007; 21(12):3250-61. DOI: 10.1096/fj.07-8218com. View

15.

Aasen T, Izpisua Belmonte J . Isolation and cultivation of human keratinocytes from skin or plucked hair for the generation of induced pluripotent stem cells. Nat Protoc. 2010; 5(2):371-82. DOI: 10.1038/nprot.2009.241. View

16.

Ogawa R, Okai K, Tokumura F, Mori K, Ohmori Y, Huang C . The relationship between skin stretching/contraction and pathologic scarring: the important role of mechanical forces in keloid generation. Wound Repair Regen. 2012; 20(2):149-57. DOI: 10.1111/j.1524-475X.2012.00766.x. View