Abstract 17845: Nucleostemin Maintains Cardiac Progenitor Cell “Stemness” and Cardiac Youth
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 with 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. This study demonstrates that NS preserves characteristics associated with “stemness” and antagonizes senescence in CPCs.
Methods & Results: Human adult failing heart CPCs (AhCPCs) exhibit decreased NS expression (-56%) relative to fetal human heart CPCs (FhCPC) correlating with lowered proliferation potential and shortened telomere length (p<0.01) AhCPC characteristics resemble CPCs isolated from old mice (OCPCs) with flat, senescent, multinucleated cell phenotype. OCPC phenotype is induced by NS silencing resulting in cell flattening, senescence, multinucleated cells, decreased S phase progression (p<0.05), diminished expression of stemness markers c-kit, Nanog, Oct4 and KLF4 with upregulation of p53 and p16 (p<0.05). CPC senescence resulting from NS loss is partially p53 dependent, as senescence acquired following NS-silencing is rescued by concurrent silencing of p53. Mechanistically, induction of NS correlates with Pim-1 kinase-mediated stabilization of c-Myc evidenced by blunted NS induction by Pim-1 in the absence of c-Myc. Engineering OCPCs and AhCPCs to overexpress NS decreases senescent and multinucleated cells, restores morphology and antagonizes senescence, thereby preserves phenotypic properties of “stemness”. Evidence supporting a role for NS in preserving myocardial structure and function was observed by characterization of heterozygous knockout mice with one functional allele of NS (NS+/-). Early cardiac aging with decline in cardiac function, increase in senescence markers p53 and p16 (p<0.05), telomere attrition (p<0.01) and accompanied CPC exhaustion was evident in NS+/- mice.
Conclusion: Youthful properties and antagonism of senescence in CPCs and the myocardium is consistent with a role for NS downstream from Pim1 signaling that enhances cardiac regeneration.
Author Disclosures: N. Hariharan: None. P. Quijada: None. A. Joyo: None. K. Samse: None. M. Monsanto: None. A. De La Torre: None. M. Sussman: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.