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

Carol A Feghali-Bostwick,Yukie Yamaguchi,Hidekata Yasuoka,Adriana T Larregina

doi:10.2174/1874312900802010017

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.

Highlights

Systemic sclerosis (SSc) is a connective tissue disease whose hallmarks include fibrosis, immune dysregulation, and vascular abnormalities
Our findings suggest that expressing Insulin-like growth factor binding proteins (IGFBPs)-5, and to a lesser extent IGFBP-3, in normal skin explants results in increased dermal thickness and increased collagen bundle thickness, recapitulating the dermal fibrosis seen in patients with SSc
These results extend our previous findings on increased IGFBP-5 and demonstrate that the increased production of IGFBP-5 in vitro by SSc fibroblasts reflects the aberrant expression in vivo

Summary

Introduction

Systemic sclerosis (SSc) is a connective tissue disease whose hallmarks include fibrosis, immune dysregulation, and vascular abnormalities. Dermal fibrosis is a prominent feature of SSc. The most commonly used mouse models of SSc are those arising from genetic mutations or treatment with bleomycin [1]. The most commonly used mouse models of SSc are those arising from genetic mutations or treatment with bleomycin [1] These murine models have proven to be useful for understanding the role of various factors in fibrosis, the ultimate goal of our research is to determine the applicability of our findings in humans who are afflicted with the disease. Comparative studies have revealed important anatomical cellular and functional differences between human and mouse skin [2]. Skin explants have been successfully used to express transgenes in both the epidermal and dermal layers for vaccination and immunotherapeutic purposes [36]

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