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Circ Res. 2011 Jan 7;108(1):51-9. doi: 10.1161/CIRCRESAHA.110.233262. Epub 2010 Nov 24.

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

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1
Department of Internal Medicine/Cardiology, UT Southwestern Medical Center, Dallas, 75390-8573, USA.

Abstract

RATIONALE:

Transgenic Notch reporter mice express enhanced green fluorescent protein in cells with C-promoter binding factor-1 response element transcriptional activity (CBF1-RE(x)₄-EGFP), providing a unique and powerful tool for identifying and isolating "Notch-activated" progenitors.

OBJECTIVE:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

A dynamic Notch injury response activates adult epicardium, producing a multipotent cell population that contributes to fibrosis repair.

Comment in

PMID:
21106942
PMCID:
PMC3042596
DOI:
10.1161/CIRCRESAHA.110.233262
[Indexed for MEDLINE]
Free PMC Article

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