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J Am Coll Cardiol. 2015 Jan 20;65(2):133-47. doi: 10.1016/j.jacc.2014.09.086.

Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging.

Author information

1
Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
2
Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California; Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
3
Section in Cardiology and Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
4
Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California. Electronic address: heartman4ever@icloud.com.

Abstract

BACKGROUND:

Functional decline in stem cell-mediated regeneration contributes to aging associated with cellular senescence in c-kit+ cardiac progenitor cells (CPCs). Clinical implementation of CPC-based therapy in elderly patients would benefit tremendously from understanding molecular characteristics of senescence to antagonize aging. Nucleostemin (NS) is a nucleolar protein regulating stem cell proliferation and pluripotency.

OBJECTIVES:

This study sought to demonstrate that NS preserves characteristics associated with "stemness" in CPCs and antagonizes myocardial senescence and aging.

METHODS:

CPCs isolated from human fetal (fetal human cardiac progenitor cell [FhCPC]) and adult failing (adult human cardiac progenitor cell [AhCPC]) hearts, as well as young (young cardiac progenitor cell [YCPC]) and old mice (old cardiac progenitor cell [OCPC]), were studied for senescence characteristics and NS expression. Heterozygous knockout mice with 1 functional allele of NS (NS+/-) were used to demonstrate that NS preserves myocardial structure and function and slows characteristics of aging.

RESULTS:

NS expression is decreased in AhCPCs relative to FhCPCs, correlating with lowered proliferation potential and shortened telomere length. AhCPC characteristics resemble those of OCPCs, which have a phenotype induced by NS silencing, resulting in cell flattening, senescence, multinucleated cells, decreased S-phase progression, diminished expression of stemness markers, and up-regulation of p53 and p16. CPC senescence resulting from NS loss is partially p53 dependent and is rescued by concurrent silencing of p53. Mechanistically, NS induction correlates with Pim-1 kinase-mediated stabilization of c-Myc. Engineering OCPCs and AhCPCs to overexpress NS decreases senescent and multinucleated cells, restores morphology, and antagonizes senescence, thereby preserving phenotypic properties of "stemness." Early cardiac aging with a decline in cardiac function, an increase in senescence markers p53 and p16, telomere attrition, and accompanied CPC exhaustion is evident in NS+/- mice.

CONCLUSIONS:

Youthful properties and antagonism of senescence in CPCs and the myocardium are consistent with a role for NS downstream from Pim-1 signaling that enhances cardiac regeneration.

KEYWORDS:

aging; senescence; signal transduction

PMID:
25593054
PMCID:
PMC4297321
DOI:
10.1016/j.jacc.2014.09.086
[Indexed for MEDLINE]
Free PMC Article

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