Abstract 16930: Asymmetric Chromatid Segregation Identifies Human Cardiac Stem Cells that Regenerate Extensively the Infarcted Myocardium
According to the immortal DNA strand hypothesis, dividing stem cells selectively segregate chromosomes carrying the old DNA template, opposing accumulation of replication errors and attenuating telomere shortening. The objective of this study was to establish whether human cardiac stem cells (hCSCs) retaining the old DNA represent more powerful cells for myocardial regeneration. We have developed a novel methodology to collect live clonal hCSCs dividing by asymmetric (old DNA) and symmetric (new DNA) chromatid segregation. Cardiac repair induced by these hCSC classes was determined in infarcted rats 15 days after cell delivery. Clonal hCSCs with old DNA led to an almost complete reconstitution of the infarct with a remarkable recovery of wall thickness-to-chamber radius ratio. hCSCs with old DNA formed 60 mm3 of human myocardium, which was 2.4-fold larger than that with hCSCs carrying the new DNA. These degrees of cardiac repair restored 82% and 38% of the infarct, respectively. The 2.2-fold higher regeneration obtained with hCSCs carrying old DNA was mediated by a parallel increase in number of new myocytes, which showed sarcomere striation, connexin 43 and N-cadherin. Similarly, the aggregate length of human arterioles and capillaries increased markedly in the reconstituted myocardium following delivery of hCSCs carrying the old DNA. The human origin of the regenerated structures was confirmed by detection of human DNA sequences with an Alu probe and human X-chromosome. Both hCSC subsets ameliorated ventricular hemodynamics. However, the recovery of cardiac performance was greater with hCSCs carrying the old DNA. To test whether the heterogeneity of the infarcted myocardium favored arrhythmia, hearts were exposed ex-vivo to electrical stimulation inducing tachycardia and fibrillation. Arrhythmic episodes were detected in 92% of infarcted untreated hearts and in 43% infarcted hearts receiving hCSCs harboring new DNA. None of the 12 hearts injected with hCSCs dividing by ACS showed tachycardia or fibrillation. Collectively, our results emphasize the role that hCSCs with old DNA have in the restoration of the structural and functional integrity of the infarcted heart, representing a superior form of cell therapy for ischemic myocardial injury.
- © 2012 by American Heart Association, Inc.