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 journalArticle

22 Scopus citations

Abstract

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 (US)
Article number6
JournalBasic research in cardiology
Volume114
Issue number2
DOIs
StatePublished - Mar 1 2019

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Mouton, A. J., Ma, Y., Rivera Gonzalez, O. J., Daseke, M. J., Flynn, E. R., Freeman, T. C., Garrett, M. R., DeLeon-Pennell, K. Y., & Lindsey, M. L. (2019). Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis. Basic research in cardiology, 114(2), [6]. https://doi.org/10.1007/s00395-019-0715-4