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

97 Citations (Scopus)

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

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Pericardium
Fibrosis
Wounds and Injuries
Severe Combined Immunodeficiency
Epithelial-Mesenchymal Transition
Response Elements
Biosensing Techniques
Gene Expression Profiling
Cell Lineage
Stromal Cells
Coculture Techniques
Cardiac Myocytes
Intercellular Signaling Peptides and Proteins
Myocardium
Flow Cytometry
Thorax
Endothelial Cells
Fibroblasts
Myocardial Infarction
Ligands

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

A dynamic notch injury response activates epicardium and contributes to fibrosis repair. / Russell, Jamie L; Goetsch, Sean C.; Gaiano, Nicholas R.; Hill, Joseph A; Olson, Eric N; Schneider, Jay W.

In: Circulation Research, Vol. 108, No. 1, 07.01.2011, p. 51-59.

Research output: Contribution to journalArticle

Russell, Jamie L ; Goetsch, Sean C. ; Gaiano, Nicholas R. ; Hill, Joseph A ; Olson, Eric N ; Schneider, Jay W. / A dynamic notch injury response activates epicardium and contributes to fibrosis repair. In: Circulation Research. 2011 ; Vol. 108, No. 1. pp. 51-59.
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