Differential expression of embryonic epicardial progenitor markers and localization of cardiac fibrosis in adult ischemic injury and hypertensive heart disease

Caitlin M. Braitsch, Onur Kanisicak, Jop H. van Berlo, Jeffery D. Molkentin, Katherine E. Yutzey

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

During embryonic heart development, the transcription factors Tcf21, Wt1, and Tbx18 regulate activation and differentiation of epicardium-derived cells, including fibroblast lineages. Expression of these epicardial progenitor factors and localization of cardiac fibrosis were examined in mouse models of cardiovascular disease and in human diseased hearts. Following ischemic injury in mice, epicardial fibrosis is apparent in the thickened layer of subepicardial cells that express Wt1, Tbx18, and Tcf21. Perivascular fibrosis with predominant expression of Tcf21, but not Wt1 or Tbx18, occurs in mouse models of pressure overload or hypertensive heart disease, but not following ischemic injury. Areas of interstitial fibrosis in ischemic and hypertensive hearts actively express Tcf21, Wt1, and Tbx18. In all areas of fibrosis, cells that express epicardial progenitor factors are distinct from CD45-positive immune cells. In human diseased hearts, differential expression of Tcf21, Wt1, and Tbx18 also is detected with epicardial, perivascular, and interstitial fibrosis, indicating conservation of reactivated developmental mechanisms in cardiac fibrosis in mice and humans. Together, these data provide evidence for distinct fibrogenic mechanisms that include Tcf21, separate from Wt1 and Tbx18, in different fibroblast populations in response to specific types of cardiac injury.

Original languageEnglish (US)
Pages (from-to)108-119
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume65
DOIs
StatePublished - Dec 2013

Bibliographical note

Funding Information:
This work was supported by a NIH/NHLBI P01HL069779 grant to KEY and JDM.

Keywords

  • Epicardium-derived cells
  • Fibrosis
  • Heart disease
  • Tbx18
  • Tcf21
  • Wt1

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