The secretome of lung resident mesenchymal stem cells is anti-fibrotic in vitro and in vivo

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by epithelial cell injury and increased numbers of fibroblasts. IPF fibroblasts have a distinct phenotype with increased type I collagen and α-smooth muscle actin (SMA) expression and enhanced Akt pathway activation. Treatment options for IPF are limited and stem cell based therapy may represent a promising new approach. Lung resident mesenchymal stem cells (MSC) have been detected in IPF lungs and their secretome/conditioned medium (CM) reduced fibroblast proliferation and enhanced epithelial wound repair via hepatocyte growth factor (HGF) in vitro. In this study we further investigated the anti-fibrotic effects of MSC-CM in vitro and in vivo. Methods: MSC were cultured from fibrotic lung tissue and the cells9 CM was collected. MSC-CM was added to IPF fibroblasts or instilled intratracheally into bleomycin-treated rats. Samples were subsequently analyzed by ELISA, TaqMan RT-PCR, immunofluorescence, immunoblotting, histology (H&S, α-SMA) or hydroxyproline assay. Results: In MSC-CM-treated IPF fibroblasts, Col1A1 expression and deposition was significantly inhibited. MMP-1 mRNA and protein was increased, whereas TIMP-1 was not affected. α-SMA mRNA and protein was significantly reduced and HGF secretion was significantly up-regulated. Akt phosphorylation was inhibited by MSC-CM between 15 min to 6h. Addition of MSC-CM to bleomycin-injured rats resulted in improved lung architecture, and reduced α-SMA and collagen content. Conclusions: Our study demonstrates that MSC-CM is anti-fibrotic in vitro and in vivo and may therefore represent a novel approach for IPF therapy. Supported by the Swiss National Research Foundation.