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Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-?-associated fibroblast activation in murine pulmonary fibrosis.

ABSTRACT: Lung fibroblasts play a pivotal role in pulmonary fibrosis, a devastating lung disease, by producing extracellular matrix. MicroRNAs (miRNAs) suppress numerous genes post-transcriptionally; however, the roles of miRNAs in activated fibroblasts in fibrotic lungs remain poorly understood. To elucidate these roles, we performed global miRNA-expression profiling of fibroblasts from bleomycin- and silica-induced fibrotic lungs and investigated the functions of miRNAs in activated lung fibroblasts. Clustering analysis of global miRNA-expression data identified miRNA signatures exhibiting increased expression during fibrosis progression. Among these signatures, we found that a miR-19a-19b-20a sub-cluster suppressed TGF-?-induced activation of fibroblasts in vitro. Moreover, to elucidate whether fibroblast-specific intervention against the sub-cluster modulates pathogenic activation of fibroblasts in fibrotic lungs, we intratracheally transferred the sub-cluster-overexpressing fibroblasts into bleomycin-treated lungs. Global transcriptome analysis of the intratracheally transferred fibroblasts revealed that the sub-cluster not only downregulated expression of TGF-?-associated pro-fibrotic genes, including Acta2, Col1a1, Ctgf, and Serpine1, but also upregulated expression of the anti-fibrotic genes Dcn, Igfbp5, and Mmp3 in activated lung fibroblasts. Collectively, these findings indicated that upregulation of the miR-19a-19b-20a sub-cluster expression in lung fibroblasts counteracted TGF-?-associated pathogenic activation of fibroblasts in murine pulmonary fibrosis.

SUBMITTER: Souma K

PROVIDER: S-EPMC6226532 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-β-associated fibroblast activation in murine pulmonary fibrosis.

Souma Kunihiko K Shichino Shigeyuki S Hashimoto Shinichi S Ueha Satoshi S Tsukui Tatsuya T Nakajima Takuya T Suzuki Hiroshi I HI Shand Francis H W FHW Inagaki Yutaka Y Nagase Takahide T Matsushima Kouji K

Scientific reports 20181109 1

Lung fibroblasts play a pivotal role in pulmonary fibrosis, a devastating lung disease, by producing extracellular matrix. MicroRNAs (miRNAs) suppress numerous genes post-transcriptionally; however, the roles of miRNAs in activated fibroblasts in fibrotic lungs remain poorly understood. To elucidate these roles, we performed global miRNA-expression profiling of fibroblasts from bleomycin- and silica-induced fibrotic lungs and investigated the functions of miRNAs in activated lung fibroblasts. Cl ...[more]

PMID: 30413725

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Project description:The B1 SOX transcription factors SOX1/2/3/19 have been implicated in various processes of early embryogenesis. However, their regulatory functions in stages from the blastula to early neurula remain largely unknown, primarily because loss-of-function studies have not been informative to date. In our present study, we systematically knocked down the B1 sox genes in zebrafish. Only the quadruple knockdown of the four B1 sox genes sox2/3/19a/19b, which are active in the early embryo, resulted in very severe developmental abnormalities, confirming that the B1 sox genes are functionally redundant. We characterized the sox2/3/19a/19b quadruple knockdown embryos in detail by examining the changes in gene expression through microarray analysis as well as in situ hybridization. Importantly, these phenotypic analyses of the quadruple knockdown embryos reveled that the B1 SOX proteins regulate the following distinct processes: (1) early dorsoventral patterning by controlling bmp2b/7; (2) gastrulation movements via the regulation of pcdh18a/18b and non-canonical wnt genes; (3) neural differentiation by regulating the Hes-class bHLH gene her3 and the proneural-class bHLH genes neurog1 (positively) and ascl1a (negatively), and regional transcription factor genes, e.g. hesx1, zic1 and rx3; and (4) neural patterning by regulating signaling pathway genes, cyp26a1 in RA signaling, oep in Nodal signaling, shh, and mdkb. These findings indicate that the B1 SOX proteins control a wide range of developmental regulators in the early embryo and suggest that the B1 sox functions are central to coordinating cell fate specification with patterning and morphogenetic processes occurring in the early embryo. Microarray analysis was carried out to compare gene expression profiles at the 30% epiboly (30%E), 75% epiboly (75%E) and tailbud (TB) stages between wild-type embryos and the sox2/3/19a/19b quadruple knockdown embryos. RNAs from two independent samples were analyzed for each embryonic stage.

Dataset Information

Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-?-associated fibroblast activation in murine pulmonary fibrosis.

Publications

Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-β-associated fibroblast activation in murine pulmonary fibrosis.

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