MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation

• Published in: American journal of respiratory cell and molecular biology Vol. 54; no. 6; pp. 843 - 852
• Main Authors: Cui, Huachun, Banerjee, Sami, Xie, Na, Ge, Jing, Liu, Rui-Ming, Matalon, Sadis, Thannickal, Victor J., Liu, Gang
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.06.2016
• Subjects: Actins - metabolism; Animals; Base Sequence; Cell Differentiation - drug effects; Collagen; Colleges & universities; Fibroblasts; Gene expression; HEK293 Cells; Humans; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - pathology; Kinases; Lentivirus - metabolism; Lungs; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Myofibroblasts - pathology; Original Research; Pathogenesis; Pulmonary fibrosis; Rodents; Smad2 Protein - metabolism; Smad4 Protein - metabolism; Transforming Growth Factor beta1 - pharmacology; α-smooth muscle actin; Smad; microRNA-27a-3p; myofibroblast; lung fibrosis
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2015-0205OC

Although microRNAs (miRs) have been well recognized to play an important role in the pathogenesis of organ fibrosis, there is a lack of evidence as to whether miRs directly regulate the differentiation of myofibroblasts, the putative effector cells during pathological fibrogenesis. In this study, we found that levels of miR-27a-3p were up-regulated in transforming growth factor-β1-treated human lung fibroblasts in a Smad2/3-dependent manner and in fibroblasts isolated from lungs of mice with experimental pulmonary fibrosis. However, both basal and transforming growth factor-β1-induced expression of miR-27a-3p were reduced in lung fibroblasts from patients with idiopathic pulmonary fibrosis compared with that from normal control subjects. Overexpression of miR-27a-3p inhibited, whereas knockdown of miR-27a-3p enhanced, the differentiation of lung fibroblasts into myofibroblasts. We found that miR-27a-3p directly targeted the phenotypic marker of myofibroblasts, α-smooth muscle actin, and two key Smad transcription factors, Smad2 and Smad4. More importantly, we found that therapeutic expression of miR-27a-3p in mouse lungs through lentiviral delivery diminished bleomycin-induced lung fibrosis. In conclusion, our data suggest that miR-27a-3p functions via a negative-feedback mechanism in inhibiting lung fibrosis. This study also indicates that targeting miR-27a-3p is a novel therapeutic approach to treat fibrotic organ disorders, including lung fibrosis.