title: Keloid-derived, plasma/fibrin-based skin equivalents generate de novo dermal and epidermal pathology of keloid fibrosis in a mouse model.
abstract: Keloids are wounding-induced tumor-like human scars. Unclear etiology and lack of animal models to reveal disease mechanisms and invent therapies deepen the grievous health and psychosocial state of vulnerable individuals. Epitomizing the injury-repair environment which triggers and fosters keloid formation and essential dermal/epidermal interactions in disease development, the novel animal model was established by implanting porous polyethylene ring-supported plasma/fibrin-based epidermal-dermal skin constructs on the dorsum of athymic NU/J mice. The implants were stable to 18 weeks, contained abundant human cells, and remodeled to yield scar architecture characteristic of keloid fibrosis compared with normal implants and clinical specimens: (1) macroscopic convex or nodular scar morphology; (2) morphogenesis and accumulation of large collagen bundles from collagen-null initial constructs; (3) epidermal hyperplasia, aberrant epidermal-dermal patency, and features of EMT; (4) increased vasculature, macrophage influx, and aggregation; and (5) temporal-spatial increased collagen-inducing PAI-1 and its interactive partner uPAR expression. Development of such pathology in the NU/J host suggests that T-cell participation is less important at this stage than at keloid initiation. These accessible implants also healed secondary excisional wounds, enabling clinically relevant contemporaneous wounding and treatment strategies, and evaluation. The model provides a robust platform for studying keloid formation and testing knowledge-based therapies.
authors.affiliation: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Yun-Shain
authors.initials: YS
authors.lastname: Lee
authors.affiliation: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Tim
authors.initials: T
authors.lastname: Hsu
authors.affiliation: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Wei-Chih
authors.initials: WC
authors.lastname: Chiu
authors.affiliation: Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Heidi
authors.initials: H
authors.lastname: Sarkozy
authors.affiliation: Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: David A
authors.initials: DA
authors.lastname: Kulber
authors.affiliation: UCLA-Orthopedic Hospital Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California.
authors.forename: Aaron
authors.initials: A
authors.lastname: Choi
authors.affiliation: UCLA-Orthopedic Hospital Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California.
authors.forename: Elliot W
authors.initials: EW
authors.lastname: Kim
authors.affiliation: UCLA-Orthopedic Hospital Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Benya
authors.affiliation: The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California.|Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Tai-Lan
authors.initials: TL
authors.lastname: Tuan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D020405:Dermis / Q000166:cytology*; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D005337:Fibrin / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D005355:Fibrosis / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D007627:Keloid / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D014183:Transplantation, Heterologous; D014945:Wound Healing / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin