Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging

Nirmala Hariharan, Pearl Quijada, Sadia Mohsin, Anya Joyo, Kaitlen Samse, Megan Monsanto, Andrea De La Torre, Daniele Avitabile, Lucia Ormachea, Michael J. McGregor, Emily J. Tsai, Mark A. Sussman

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)133-147
Number of pages15
JournalJournal of the American College of Cardiology
Volume65
Issue number2
DOIs
Publication statusPublished - 2015

Keywords

  • Aging
  • Senescence
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Hariharan, N., Quijada, P., Mohsin, S., Joyo, A., Samse, K., Monsanto, M., De La Torre, A., Avitabile, D., Ormachea, L., McGregor, M. J., Tsai, E. J., & Sussman, M. A. (2015). Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. Journal of the American College of Cardiology, 65(2), 133-147. https://doi.org/10.1016/j.jacc.2014.09.086