title: Reversal of the Transcriptome by Prostaglandin E2 during Myofibroblast Dedifferentiation.
abstract: Myofibroblasts, the major effector cells in pathologic fibrosis, derive from the differentiation of fibroblasts driven by mediators such as transforming growth factor-β1 (TGF-β1) and biomechanical signals. Although the myofibroblast has traditionally been considered a terminally differentiated cell, the lipid mediator prostaglandin E2 (PGE2) has been shown to not only prevent but also reverse myofibroblast differentiation, as characterized by the ability of PGE2 to diminish expression of collagen I and α-smooth muscle actin in established myofibroblasts. Here, we use microarrays to examine the extent of transcriptomic changes that occur during TGF-β1-induced differentiation and PGE2-induced dedifferentiation of myofibroblasts. Normal primary human adult lung fibroblasts were cultured for 24 hours with or without TGF-β1 and treated for 48 hours with PGE2. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. TGF-β1 up-regulated 588 genes and down-regulated 689 genes compared with control cells. PGE2 reversed the expression of 363 (62%) of the TGF-β1-up-regulated genes and 345 (50%) of the TGF-β1-down-regulated genes. Genes up-regulated by TGF-β1 and reversed by PGE2 were enriched in annotations for Cell Adhesion, Contractile Fiber, and Actin Binding, whereas genes down-regulated by TGF-β1 but subsequently reversed by PGE2 were enriched in annotations for Glycoprotein, Polysaccharide Binding, and Regulation of Cell Migration. Surprisingly, the genes whose expression was affected by PGE2 differed between TGF-β1-induced myofibroblasts and undifferentiated fibroblasts. These data demonstrate the capacity of PGE2 to effect marked global alterations in the transcriptomic program of differentiated myofibroblasts and emphasize the considerable plasticity of these cells.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine in the Department of Internal Medicine and.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Wettlaufer
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine in the Department of Internal Medicine and.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Scott
authors.affiliation: 2 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Richard C
authors.initials: RC
authors.lastname: McEachin
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine in the Department of Internal Medicine and.
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine in the Department of Internal Medicine and.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Huang
mesh_terms: D002460:Cell Line; D054338:Cell Transdifferentiation / Q000187:drug effects* / Q000235:genetics; D015232:Dinoprostone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005838:Genotype; D006801:Humans; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D060066:Protein Interaction Maps; D015398:Signal Transduction; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D053773:Transforming Growth Factor beta1; D015232:Dinoprostone
keywords: fibroblasts; microarray; prostaglandin E2; pulmonary fibrosis; transforming growth factor β1