title: miRNA-146a expression positively regulates tumor necrosis factor-α-induced interleukin-8 production in mesenchymal stem cells and differentiated lung epithelial-like cells.
abstract: Bone marrow-derived mesenchymal stem cells (BM-MSC) can be differentiated into lung epithelial-like cells (MSC-EC) in vitro. The response of BM-MSC and MSC-EC to stimuli may vary because of their character and differentiation. We aimed to investigate the factors that may influence in vitro differentiation of BM-MSC to MSC-EC. We determined the response of BM-MSC, MSC-EC, bronchial epithelial cells, and alveolar epithelial cells to tumor necrosis factor (TNF)-α stimulation. We also investigated the changes in micro(mi)RNA-146a, miRNA-155, and TNF receptor 1 (TNFR1) expression after stimulation. Our results demonstrate that the addition of transforming growth factor-β(1) and extracellular matrix collagen are required to facilitate such differentiation. After 3 weeks of culture, the morphological appearance and expression of airway epithelial markers, cytokeratin and Clara cell secretory protein, in MSC-EC were characteristics of lung epithelial cells. In response to TNF-α stimulation, the maximal interleukin (IL)-8 production by BM-MSC at the 24-h time point was 4.8 times greater compared with MSC-EC. TNF-α induced a significant increase in the expression of miRNA-146a in BM-MSC as compared with MSC-EC. miRNA-155 expression remained unchanged after stimulation. TNFR1 mRNA also significantly increased in BM-MSC after TNF-α stimulation. This was not observed in MSC-EC. Transfection with miRNA-146a mimics resulted in a significant increase of miRNA-146a expression and IL-8 production in both types of cells. In contrast, miRNA-146a inhibitors reduced miRNA-146a expression and IL-8 production. Overexpression of miRNA-146a, which positively regulates TNF-α-induced IL-8 release, may enhance the inflammatory response in both BM-MSC and MSC-EC. The expression of miRNA-146a and the response to stimuli may be modulated through mature differentiation of BM-MSC.
authors.affiliation: Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. dwperng@vghtpe.gov.tw
authors.forename: Diahn-warng
authors.initials: DW
authors.lastname: Perng
authors.forename: De-ming
authors.initials: DM
authors.lastname: Yang
authors.forename: Yi-han
authors.initials: YH
authors.lastname: Hsiao
authors.forename: Ting
authors.initials: T
authors.lastname: Lo
authors.forename: Oscar Kuang-sheng
authors.initials: OK
authors.lastname: Lee
authors.forename: Mo-tzu
authors.initials: MT
authors.lastname: Wu
authors.forename: Yu-chung
authors.initials: YC
authors.lastname: Wu
authors.forename: Yu-chin
authors.initials: YC
authors.lastname: Lee
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008168:Lung / Q000166:cytology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D015415:Biomarkers; D016209:Interleukin-8; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048052:Mitogen-Activated Protein Kinase 3