Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

Alan J Mouton, Yonggang Ma, Osvaldo J Rivera Gonzalez, Michael J Daseke, Elizabeth R Flynn, Tom C Freeman, Michael R Garrett, Kristine Y DeLeon-Pennell, Merry L Lindsey

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Cardiac fibroblasts are the major producers of extracellular matrix (ECM) to form infarct scar. We hypothesized that fibroblasts undergo a spectrum of phenotype states over the course of myocardial infarction (MI) from early onset to scar formation. Fibroblasts were isolated from the infarct region of C57BL/6J male mice (3-6 months old, n = 60) at days 0 (no MI control) and 1, 3, or 7 after MI. Whole transcriptome analysis was performed by RNA-sequencing. Of the genes sequenced, 3371 were differentially expressed after MI. Enrichment analysis revealed that MI day 1 fibroblasts displayed pro-inflammatory, leukocyte-recruiting, pro-survival, and anti-migratory phenotype through Tnfrsf9 and CD137 signaling. MI day 3 fibroblasts had a proliferative, pro-fibrotic, and pro-angiogenic profile with elevated Il4ra signaling. MI day 7 fibroblasts showed an anti-angiogenic homeostatic-like myofibroblast profile and with a step-wise increase in Acta2 expression. MI day 7 fibroblasts relied on Pik3r3 signaling to mediate Tgfb1 effects and Fgfr2 to regulate PI3K signaling. In vitro, the day 3 MI fibroblast secretome stimulated angiogenesis, while day 7 MI fibroblast secretome repressed angiogenesis through Thbs1 signaling. Our results reveal novel mechanisms for fibroblasts in expressing pro-inflammatory molecules and regulating angiogenesis following MI.

Original languageEnglish
Pages (from-to)6
JournalBasic research in cardiology
Volume114
Issue number2
DOIs
Publication statusPublished - 11 Jan 2019

Keywords / Materials (for Non-textual outputs)

  • Myocardial infarction
  • Cardiac remodeling
  • Fibroblast
  • Transcriptome
  • Angiogenesis
  • Extracellular matrix

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