Journal Article

Amnion Epithelial Cell‐Derived Exosomes Restrict Lung Injury and Enhance Endogenous Lung Repair

Lim, Rebecca, Saad, Mohamed I., Kim, Carla, Zhu, Dandan, Lau, Sin N., Krause, Mirja, Salamonsen, Lois A., Leaw, Bryan, Chan, Siow T., Nguyen, Hong P. T., Sievert, William, Wallace, Euan M., Tan, Jean L.

2018

Overview

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation, severe scarring, and stem cell senescence. Stem cell‐based therapies modulate inflammatory and fibrogenic pathways by release of soluble factors. Stem cell‐derived extracellular vesicles should be explored as a potential therapy for IPF. Human amnion epithelial cell‐derived exosomes (hAEC Exo) were isolated and compared against human lung fibroblasts exosomes. hAEC Exo were assessed as a potential therapy for lung fibrosis. Exosomes were isolated and evaluated for their protein and miRNA cargo. Direct effects of hAEC Exo on immune cell function, including macrophage polarization, phagocytosis, neutrophil myeloperoxidase activity and T cell proliferation and uptake, were measured. Their impact on immune response, histological outcomes, and bronchioalveolar stem cell (BASC) response was assessed in vivo following bleomycin challenge in young and aged mice. hAEC Exo carry protein cargo enriched for MAPK signaling pathways, apoptotic and developmental biology pathways and miRNA enriched for PI3K‐Akt, Ras, Hippo, TGFβ, and focal adhesion pathways. hAEC Exo polarized and increased macrophage phagocytosis, reduced neutrophil myeloperoxidases, and suppressed T cell proliferation directly. Intranasal instillation of 10 μg hAEC Exo 1 day following bleomycin challenge reduced lung inflammation, while treatment at day 7 improved tissue‐to‐airspace ratio and reduced fibrosis. Administration of hAEC Exo coincided with the proliferation of BASC. These effects were reproducible in bleomycin‐challenged aged mice. The paracrine effects of hAECs can be largely attributed to their exosomes and exploitation of hAEC Exo as a therapy for IPF should be explored further. Stem Cells Translational Medicine 2018;7:180–196 Human amnion epithelial cells (hAECs) possess potent reparative and regenerative properties, especially in experimental models of lung fibrosis. It is now evident that these mechanism may be attributed to secretory factors released by hAECs termed exosomes. These hAEC Exo can be isolated with high purity through differential ultracentrifugation. Transmission electron microscopy shows exosomes of typical cup‐shaped morphology, intracellular and outward budding vesicles from hAECs (Scale bar = 100 nm). Administration of 10 μg of hAEC Exo into bleomycin challenged mice ameliorated fibroblast activated αSMA positive cells (Scale bar = 50 μm) and increased lung progenitor cell renewal seen through expression of CC10+/SPC+ dual positive staining for bronchioalveolar stem cells (Scale bar = 50 μm).

• Publisher: Oxford University Press,John Wiley and Sons Inc
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Amnion / Amnion - cytology / Amniotic Stem Cells / Animals / Apoptosis / Bleomycin / Cell cycle / Cell proliferation / Cell Proliferation - physiology / Cells, Cultured / Cell‐free Systems / Developmental biology / Disease Models (Animal/Cell) / Epithelial cells / Epithelial Cells - cytology / Exosomes / Exosomes - physiology / Female / Fetal and Neonatal Stem Cells / Fetal stem cells / Fibroblasts / Fibroblasts - pathology / Fibrosis / Flow cytometry / Gene expression / Humans / Inflammation / Inflammation / Inflammatory Disease / Kinases / Lung / Lung - pathology / Lung diseases / Lung Injury - pathology / Lung Stem Cells / Lymphocytes T / Macrophages / MAP kinase / Medical prognosis / Mice / Mice, Inbred C57BL / MicroRNAs / Microscopy / miRNA / Morphology / Mortality / Neutrophils - physiology / Paracrine signalling / Peroxidase / Phagocytosis / Pneumonia - pathology / Pregnancy / Progenitor cells / Proteins / Pulmonary fibrosis / Pulmonary Fibrosis - pathology / Senescence / Signal transduction / Signal Transduction - physiology / Stem Cell Niche / Stem cell transplantation / Stem cells / T cells / T-Lymphocytes - physiology / Tissue‐specific stem cells / Translational s and Reviews / Transplantation