Induction of Scleroderma Fibrosis in Skin-Humanized Mice by Administration of Anti-Platelet-Derived Growth Factor Receptor Agonistic Autoantibodies.
To describe a skin-SCID mouse chimeric model of systemic sclerosis (SSc; scleroderma) fibrosis based on engraftment of ex vivo-bioengineered skin using skin cells derived either from scleroderma patients or from healthy donors.



Three-dimensional bioengineered skin containing human keratinocytes and fibroblasts isolated from skin biopsy specimens from healthy donors or SSc patients was generated ex vivo and then grafted onto the backs of SCID mice. The features of the skin grafts were analyzed by immunohistochemistry, and the functional profile of the graft fibroblasts was defined before and after treatment with IgG from healthy controls or SSc patients. Two procedures were used to investigate the involvement of platelet-derived growth factor receptor (PDGFR): 1) nilotinib, a tyrosine kinase inhibitor, was administered to mice before injection of IgG from SSc patient sera (SSc IgG) into the grafts, and 2) human anti-PDGFR monoclonal antibodies were injected into the grafts.



Depending on the type of bioengineered skin grafted, the regenerated human skin exhibited either the typical scleroderma phenotype or the healthy human skin architecture. Treatment of animals carrying healthy donor skin grafts with SSc IgG resulted in the appearance of a bona fide scleroderma phenotype, as confirmed by increased collagen deposition and fibroblast activation markers. Results of the experiments involving administration of nilotinib or monoclonal antibodies confirmed the involvement of PDGFR.



Our results provide the first in vivo demonstration of the fibrotic properties of anti-PDGFR agonistic antibodies. This bioengineered skin-humanized mouse model can be used to test in vivo the progression of the disease and to monitor response to antifibrotic drugs.
Università Politecnica delle Marche, Ancona, Italy.
Michele M
0000-0001-9132-7401
MM
Luchetti
Università Politecnica delle Marche, Ancona, Italy.
Gianluca
G
Moroncini
Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras and Instituto de Investigaciones Sanitarias dela Fundacion Jimenez Diaz, Madrid, Spain.
Maria
M
Jose Escamez
Università Politecnica delle Marche, Ancona, Italy.
Silvia
S
Svegliati Baroni
Università Politecnica delle Marche, Ancona, Italy.
Tatiana
T
Spadoni
Università Politecnica delle Marche, Ancona, Italy.
Antonella
A
Grieco
Università Politecnica delle Marche, Ancona, Italy.
Chiara
C
Paolini
Università di Torino, Turin, Italy.
Ada
A
Funaro
Università Federico II, Naples, Italy.
Enrico V
EV
Avvedimento
Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras and Instituto de Investigaciones Sanitarias dela Fundacion Jimenez Diaz, Madrid, Spain.
Fernando
F
Larcher
Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras and Instituto de Investigaciones Sanitarias dela Fundacion Jimenez Diaz, Madrid, Spain.
Marcela
M
Del Rio
Università Politecnica delle Marche, Ancona, Italy.
Armando
A
Gabrielli
D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D017479:Receptors, Platelet-Derived Growth Factor / Q000276:immunology*; D012594:Scleroderma, Localized / Q000276:immunology* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000473:pathology; D012867:Skin / Q000276:immunology
D001323:Autoantibodies; D017479:Receptors, Platelet-Derived Growth Factor