Abstract
IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic lung disease, resulting in respiratory insufficiency and reduced survival. Pulmonary fibrosis is a result of repeated alveolar epithelial microinjuries, followed by abnormal regeneration and repair processes in the lung. Recently, stem cells and their secretome have been investigated as a novel therapeutic approach in pulmonary fibrosis. We evaluated the potential of induced pluripotent stem cells (iPSC) conditioned media (iPSC-cm) to regenerate and repair the alveolar epithelium in vitro and improve bleomycin induced lung injury in vivo.MethodsIPSC-cm was collected from cultured iPSC derived from human foreskin fibroblasts and its biological effects on alveolar epithelial wound repair was studied in an alveolar wound healing assay in vitro. Furthermore, iPSC-cm was intratracheally instilled 7 days after bleomycin induced injury in the rat lungs and histologically and biochemically assessed 7 days after instillation.ResultsiPSC-cm increased alveolar epithelial wound repair in vitro compared with medium control. Intratracheal instillation of iPSC-cm in bleomycin-injured lungs reduced the collagen content and improved lung fibrosis in the rat lung in vivo. Profibrotic TGFbeta1 and α-smooth muscle actin (α-sma) expression were markedly reduced in the iPSC-cm treated group compared with control. Antifibrotic hepatocyte growth factor (HGF) was detected in iPSC-cm in biologically relevant levels, and specific inhibition of HGF in iPSC-cm attenuated the antifibrotic effect of iPSC-cm, indicating a central role of HGF in iPSC-cm.ConclusioniPSC-cm increased alveolar epithelial wound repair in vitro and attenuated bleomycin induced fibrosis in vivo, partially due to the presence of HGF and may represent a promising novel, cell free therapeutic option against lung injury and fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1186/scrt513) contains supplementary material, which is available to authorized users.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic lung disease, resulting in respiratory insufficiency and reduced survival
In the present study we show that induced pluripotent stem cells (iPSC)-cm may be a novel and promising source of cell-based yet cell-free therapy for pulmonary fibrosis, since induced pluripotent stem cell conditioned medium (iPSC-cm) induces alveolar epithelial repair in vitro and reduces lung fibrosis in a bleomycin-induced animal model in vivo, at least in part by a hepatocyte growth factor (HGF)-dependent mechanism
Induced pluripotent stem cells grow well during preparation of conditioned media Annexin–Propidium iodide (PI) staining of the iPSCs growing in serum replacement and β-fibroblast growth factor (bFGF)-free media revealed no drastic cell death
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic lung disease, resulting in respiratory insufficiency and reduced survival. Cell-based approaches have been proposed recently as new possibilities to regenerate various organs [4,5,6,7], including the fibrotic lung [8,9]. This usually implies administration of exogenously derived stem cells that support regeneration and modulate the progress of the disease. The isolation and expansion of these cells is well established, there are some concerns with regards to their efficiency and availability, in older patients [13] Another obvious source is embryonic stem cells, but the complexity of the derivation technique and ethical issues have hindered advancement in clinical applications. IPSCs have been successfully used for regeneration in spinal injury, cerebral vascular injury and acute lung injury in animal models [17,18,19], providing evidence that iPSCs could be very promising candidates for cell-based therapies in a variety of diseases
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