title: Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Hariharan
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Anya
authors.initials: A
authors.lastname: Joyo
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Kaitlen
authors.initials: K
authors.lastname: Samse
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Megan
authors.initials: M
authors.lastname: Monsanto
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Andrea
authors.initials: A
authors.lastname: De La Torre
authors.affiliation: 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.
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ormachea
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGregor
authors.affiliation: Section in Cardiology and Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Tsai
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California. Electronic address: heartman4ever@icloud.com.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D019204:GTP-Binding Proteins; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis*; D016601:RNA-Binding Proteins; D012060:Rejuvenation / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C470311:nucleostemin protein, mouse; D019204:GTP-Binding Proteins
keywords: aging; senescence; signal transduction