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Lung Mesenchymal Stem Cell-Derived PGE2 Increases the Secretion of Anti-Fibrotic HGF by IPF Fibroblasts
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A2193 - Lung Mesenchymal Stem Cell-Derived PGE2 Increases the Secretion of Anti-Fibrotic HGF by IPF Fibroblasts
Author Block: P. Khan1, A. Gazdhar2, T. Geiser2, M. Roth1, M. Tamm1, K. E. Hostettler1; 1Department of Biomedicine, University Hospital, Basel, Switzerland, 2Division of Pulmonary Medicine, University Hospital, Bern, Switzerland.
Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by repetitive injury to alveolar epithelial cells, an increased fibroblast activation and extracellular matrix deposition. Therapeutic options for IPF are limited and stem cell based therapy offers a promising new approach. Mesenchymal stem cells (MSC) are present in the lungs of IPF patients and their secretome has been shown to increase epithelial wound repair via hepatocyte growth factor (HGF) in vitro. Furthermore, HGF-over expressing MSC inhibited bleomycin-induced lung fibrosis in rats. In this study we investigated the effect of lung MSC-conditioned medium (CM) on the secretion of anti-fibrotic HGF by IPF fibroblasts and aimed to identify involved mediators. Methods: MSC were cultured from lung tissue obtained from patients with fibrotic lung diseases. Tissue derived from IPF patients was used to culture fibroblasts. HGF and prostaglandin (PG) E2 levels were measured by ELISA and a cytokine array was used to detect secreted cytokines in MSC-CM. Results: MSC-CM (n=8) significantly increased the secretion of HGF by IPF fibroblasts from 13125 pg/ml in the medium control group to 25205 pg/ml in MSC-CM treated IPF fibroblasts. Using a cytokine array (n=3) we could show that MSC secrete several cytokines including high levels of IL-6, IL-8, ENA-78 or GDF-15. However, when IPF fibroblasts were treated with human recombinant cytokines (IL-6, IL-8, ENA-78, GDF-15, osteopontin, IL-17A, GM-CSF, GROα) that were present in the MSC-CM, none of them increased HGF secretion by fibroblasts (n=3). PGE2, a known inducer of HGF, was present in MSC-CM at levels of 3034 pg/ml (n=36). Interestingly, recombinant PGE2 dose-dependently up-regulated HGF secretion by IPF fibroblasts between 10-1000 nM (n=4). Importantly, when IPF fibroblasts were pre-treated with the PGE2 receptor antagonists AH6809 (20 μM) or PF04418948 (1 or 10 μM), MSC-CM-induced HGF secretion by fibroblasts was significantly reversed (n=4). In addition, when PGE2 production by MSC was blocked by MSC treatment with COX inhibitor indomethacin (1 or 10 μM), MSC-CM-induced HGF secretion by fibroblasts was completely abrogated (n=4). Conclusions: Our study demonstrated that MSC-CM increases the secretion of HGF by IPF fibroblasts via PGE2. MSC-CM may therefore serve as a new therapeutic approach that may help to positively regulate HGF-dependent epithelial wound repair in IPF.
Author Block: P. Khan1, A. Gazdhar2, T. Geiser2, M. Roth1, M. Tamm1, K. E. Hostettler1; 1Department of Biomedicine, University Hospital, Basel, Switzerland, 2Division of Pulmonary Medicine, University Hospital, Bern, Switzerland.
Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by repetitive injury to alveolar epithelial cells, an increased fibroblast activation and extracellular matrix deposition. Therapeutic options for IPF are limited and stem cell based therapy offers a promising new approach. Mesenchymal stem cells (MSC) are present in the lungs of IPF patients and their secretome has been shown to increase epithelial wound repair via hepatocyte growth factor (HGF) in vitro. Furthermore, HGF-over expressing MSC inhibited bleomycin-induced lung fibrosis in rats. In this study we investigated the effect of lung MSC-conditioned medium (CM) on the secretion of anti-fibrotic HGF by IPF fibroblasts and aimed to identify involved mediators. Methods: MSC were cultured from lung tissue obtained from patients with fibrotic lung diseases. Tissue derived from IPF patients was used to culture fibroblasts. HGF and prostaglandin (PG) E2 levels were measured by ELISA and a cytokine array was used to detect secreted cytokines in MSC-CM. Results: MSC-CM (n=8) significantly increased the secretion of HGF by IPF fibroblasts from 13125 pg/ml in the medium control group to 25205 pg/ml in MSC-CM treated IPF fibroblasts. Using a cytokine array (n=3) we could show that MSC secrete several cytokines including high levels of IL-6, IL-8, ENA-78 or GDF-15. However, when IPF fibroblasts were treated with human recombinant cytokines (IL-6, IL-8, ENA-78, GDF-15, osteopontin, IL-17A, GM-CSF, GROα) that were present in the MSC-CM, none of them increased HGF secretion by fibroblasts (n=3). PGE2, a known inducer of HGF, was present in MSC-CM at levels of 3034 pg/ml (n=36). Interestingly, recombinant PGE2 dose-dependently up-regulated HGF secretion by IPF fibroblasts between 10-1000 nM (n=4). Importantly, when IPF fibroblasts were pre-treated with the PGE2 receptor antagonists AH6809 (20 μM) or PF04418948 (1 or 10 μM), MSC-CM-induced HGF secretion by fibroblasts was significantly reversed (n=4). In addition, when PGE2 production by MSC was blocked by MSC treatment with COX inhibitor indomethacin (1 or 10 μM), MSC-CM-induced HGF secretion by fibroblasts was completely abrogated (n=4). Conclusions: Our study demonstrated that MSC-CM increases the secretion of HGF by IPF fibroblasts via PGE2. MSC-CM may therefore serve as a new therapeutic approach that may help to positively regulate HGF-dependent epithelial wound repair in IPF.
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