A dynamic notch injury response activates epicardium and contributes to fibrosis repair.

Jamie L Russell, Sean C. Goetsch, Nicholas R. Gaiano, Joseph A Hill, Eric N Olson, Jay W Schneider

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Transgenic Notch reporter mice express enhanced green fluorescent protein in cells with C-promoter binding factor-1 response element transcriptional activity (CBF1-RE(x)-EGFP), providing a unique and powerful tool for identifying and isolating "Notch-activated" progenitors. We asked whether, as in other tissues of this mouse, EGFP localized and functionally tagged adult cardiac tissue progenitors, and, if so, whether this cell-based signal could serve as a quantitative and qualitative biosensor of the injury repair response of the heart. In addition to scattered endothelial and interstitial cells, Notch-activated (EGFP(+)) cells unexpectedly richly populated the adult epicardium. We used fluorescence-activated cell sorting to isolate EGFP(+) cells and excluded hematopoietic (CD45(+)) and endothelial (CD31(+)) subsets. We analyzed EGFP(+)/CD45/CD31 cells, a small (<2%) but distinct subpopulation, by gene expression profiling and functional analyses. We called this mixed cell pool, which had dual multipotent stromal cell and epicardial lineage signatures, Notch-activated epicardial-derived cells (NECs). Myocardial infarction and thoracic aortic banding amplified the NEC pool, increasing fibroblast differentiation. Validating the functional vitality of clonal NEC lines, serum growth factors triggered epithelial-mesenchymal transition and the immobilized Notch ligand Delta-like 1-activated downstream target genes. Moreover, cardiomyocyte coculture and engraftment in NOD-SCID (nonobese diabetic-severe combined immunodeficiency) mouse myocardium increased cardiac gene expression in NECs. A dynamic Notch injury response activates adult epicardium, producing a multipotent cell population that contributes to fibrosis repair.

Original languageEnglish (US)
Pages (from-to)51-59
Number of pages9
JournalCirculation research
Volume108
Issue number1
DOIs
StatePublished - Jan 7 2011

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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