Sca-1 + cardiac fibroblasts promote development of heart failure

Guobao Chen, William Bracamonte-Baran, Nicola L. Diny, Xuezhou Hou, Monica V. Talor, Kai Fu, Yue Liu, Giovanni Davogustto, Hernan Vasquez, Heinrich Taegtmeyer, O. Howard Frazier, Ari Waisman, Simon J. Conway, Fengyi Wan, Daniela Čiháková

Research output: Contribution to journalArticle

Abstract

The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45 CD31 CD29 + mEF-SK4 + PDGFRα + Sca-1 + periostin + (Sca-1 + ) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1 + periostin + cardiac fibroblasts (Postn Cre Il17ra fl/fl ) protected mice from post-infarct heart failure and death. Moreover, Postn Cre Il17ra fl/fl mice had significantly fewer GM-CSF-producing Sca-1 + cardiac fibroblasts and inflammatory Ly6C hi monocytes in the heart. Sca-1 + cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM-CSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM-CSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1 + cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.

Original languageEnglish (US)
Pages (from-to)1522-1538
Number of pages17
JournalEuropean Journal of Immunology
Volume48
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • Fibroblasts
  • GM-CSF
  • Heart failure
  • IL-17
  • Myocarditis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Chen, G., Bracamonte-Baran, W., Diny, N. L., Hou, X., Talor, M. V., Fu, K., Liu, Y., Davogustto, G., Vasquez, H., Taegtmeyer, H., Frazier, O. H., Waisman, A., Conway, S. J., Wan, F., & Čiháková, D. (2018). Sca-1 + cardiac fibroblasts promote development of heart failure European Journal of Immunology, 48(9), 1522-1538. https://doi.org/10.1002/eji.201847583