Human Skin Culture as an Ex Vivo Model for Assessing the Fibrotic Effects of Insulin-Like Growth Factor Binding Proteins



Hidekata Yasuoka1, Adriana T. Larregina2, Yukie Yamaguchi1, Carol A. Feghali-Bostwick*, 1, 3
Department of 1 Medicine
Department of 2 Dermatology, 2 Immunology and
Department of 3 Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA


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open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

* Address correspondence to this author at the University of Pittsburgh, Division of Pulmonary, Allergy, and Critical Care Medicine, 628 NW Montefiore, 3459 Fifth Ave., Pittsburgh, PA, 15213, USA; Tel.: 412-692-2210; Fax: 412-692-2260; E-mail: feghalica@upmc.edu


Abstract

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. A hallmark of SSc is fibrosis of the skin and internal organs. We recently demonstrated increased expression of IGFBP-3 and IGFBP-5 in primary cultures of fibroblasts from the skin of patients with SSc. In vitro, IGFBP-3 and IGFBP-5 induced a fibrotic phenotype and IGFBP-5 triggered dermal fibrosis in mice. To assess the ability of IGFBPs to trigger fibrosis, we used an ex vivo human skin organ culture model. Our findings demonstrate that IGFBP-3 and IGFBP-5, but not IGFBP-4, increase dermal and collagen bundle thickness in human skin explants, resulting in substantial dermal fibrosis and thickening. These fibrotic effects were sustained for at least two weeks. Our findings demonstrate that human skin ex vivo is an appropriate model to assess the effects of fibrosis-inducing factors such as IGFBPs, and for evaluating the efficacy of inhibitors/therapies to halt the progression of fibrosis and potentially reverse it.