Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / biosynthesis*
  • Cell Differentiation
  • Cells, Cultured
  • Cellular Senescence / physiology*
  • GTP-Binding Proteins
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Myocardium / cytology*
  • Myocardium / metabolism
  • Nuclear Proteins / biosynthesis*
  • RNA-Binding Proteins
  • Rejuvenation / physiology*
  • Stem Cells / cytology*
  • Stem Cells / metabolism


  • Carrier Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • nucleostemin protein, mouse
  • GTP-Binding Proteins