title: Tracking chromatid segregation to identify human cardiac stem cells that regenerate extensively the infarcted myocardium.
abstract: BACKGROUND
  According to the immortal DNA strand hypothesis, dividing stem cells selectively segregate chromosomes carrying the old template DNA, opposing accumulation of mutations resulting from nonrepaired replication errors and attenuating telomere shortening.
  
  
  OBJECTIVE
  Based on the premise of the immortal DNA strand hypothesis, we propose that stem cells retaining the old DNA would represent the most powerful cells for myocardial regeneration.
  
  
  RESULTS
  Division of human cardiac stem cells (hCSCs) by nonrandom and random segregation of chromatids was documented by clonal assay of bromodeoxyuridine-tagged hCSCs. Additionally, their growth properties were determined by a series of in vitro and in vivo studies. We report that a small class of hCSCs retain during replication the mother DNA and generate 2 daughter cells, which carry the old and new DNA, respectively. hCSCs with immortal DNA form a pool of nonsenescent cells with longer telomeres and higher proliferative capacity. The self-renewal and long-term repopulating ability of these cells was shown in serial-transplantation assays in the infarcted heart; these cells created a chimeric organ, composed of spared rat and regenerated human cardiomyocytes and coronary vessels, leading to a remarkable restoration of cardiac structure and function. The documentation that hCSCs divide by asymmetrical and symmetrical chromatid segregation supports the view that the human heart is a self-renewing organ regulated by a compartment of resident hCSCs.
  
  
  CONCLUSIONS
  The impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this stem cell class for the management of heart failure in humans.
authors.affiliation: Departments of Anesthesia and Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. jkajstura@partners.org
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Bai
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.forename: Junghyun
authors.initials: J
authors.lastname: Kim
authors.forename: Christian
authors.initials: C
authors.lastname: Arranto
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Amario
authors.forename: Alex
authors.initials: A
authors.lastname: Matsuda
authors.forename: Silvana
authors.initials: S
authors.lastname: Bardelli
authors.forename: João
authors.initials: J
authors.lastname: Ferreira-Martins
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002842:Chromatids / Q000502:physiology* / Q000648:ultrastructure; D020090:Chromosome Segregation / Q000502:physiology*; D004247:DNA / Q000502:physiology; D005260:Female; D006321:Heart / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D011916:Rats, Inbred F344; D012038:Regeneration / Q000502:physiology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D016615:Telomere / Q000648:ultrastructure; D055815:Young Adult
chemical_list: D004247:DNA; D001973:Bromodeoxyuridine