title: Fibrotic myofibroblasts manifest genome-wide derangements of translational control.
abstract: BACKGROUND
  As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast-the primary effector of the fibroproliferative response. We have recently shown that aberrant beta 1 integrin signaling in fibrotic fibroblasts results in defective PTEN function, unrestrained Akt signaling and subsequent activation of the translation initiation machinery. How this pathological integrin signaling alters the gene expression pathway has not been elucidated.
  
  
  RESULTS
  Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF-beta -driven EMT as one source of IPF myofibroblasts.
  
  
  CONCLUSIONS
  These findings establish the power of systems level genome-wide analysis to provide mechanistic insights into fibrotic disorders such as IPF. Our data point to derangements of translational control downstream of aberrant beta 1 integrin signaling as a fundamental component of IPF pathobiology and indicates that TGF-beta -driven EMT is one source for IPF myofibroblasts.
authors.affiliation: Pulmonary Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America. ola.larsson@mail.mcgill.ca
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Deanna
authors.initials: D
authors.lastname: Diebold
authors.forename: Danhua
authors.initials: D
authors.lastname: Fan
authors.forename: Mark
authors.initials: M
authors.lastname: Peterson
authors.forename: Richard Seonghun
authors.initials: RS
authors.lastname: Nho
authors.forename: Peter B
authors.initials: PB
authors.lastname: Bitterman
authors.forename: Craig A
authors.initials: CA
authors.lastname: Henke
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015894:Genome, Human; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D014176:Protein Biosynthesis; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism*; D012270:Ribosomes / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D016212:Transforming Growth Factor beta
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