How old is your heart?

The traditional concept of the heart as a terminally differentiated postmitotic organ has been largely based on an influential study published in 1925 that reported the paucity or near-absence of cell division and mitosis in the human heart, which was in striking contrast with the regenerative capacity of eg, liver tissue.1 Additional arguments thought to support this concept are the absence of significant tissue regeneration after damage such as myocardial infarction and the response to increased demand of the heart by hypertrophy of cells, rather than by hyperplasia. This concept was, however, challenged a number of years ago. Using improved imaging methods for apoptosis, mitosis, and cellular senescence, Anversa and colleagues provided new quantitative data well beyond what had been reported before; cardiac cells were shown to be capable to reenter the replicative phase, and the incidence of mitotic figures was increased several-fold in the failing heart.2–4 These observations, together with the demonstration of host male cells in gender-mismatched human cardiac transplant recipients,5 formed the basis for developing a new concept of the heart as a dynamic, potentially self-renewing organ. Generation of new myocytes was reported to contribute to remodeling processes.6 Several studies in support of this new paradigm provided evidence for cell division using microscopic confocal imaging. Interestingly, these replicating cells showed a much smaller volume than fully differentiated cardiac myocytes, and it seemed unlikely that the latter would reenter the cell cycle. Subsequently, confocal analysis as well as improved cell isolation and separation techniques identified the existence of cardiac stem cells (CSC) distributed in small clusters between cardiomyocytes.7,8 When isolated and cultured under specific conditions, these cells can differentiate into myocytes, smooth muscle, and endothelial cells. CSC with cardiogenic potential and capable of cardiac repair were recently also isolated from small endomyocardial biopsies of human hearts.9 Such cells could represent the reservoir for continuous self-renewal, and could potentially be harnessed to provide for the much-needed tissue repair after myocardial infarction. However, cardiac stem cells lack migratory and homing capacity to translocate to sites of injury but were recently reported to respond to essential growth factors that facilitate migration (hepatocyte growth factor [HGF]) and survival in an ischemic microenvironment (insulin-like growth factor-1 [IGF-1]).10 Local injection of these growth factors in the myocardium of mice 5 hours after myocardial infarction and 2 days after retroviral inoculation with enhanced green fluorescence protein (EGFP, to tag cycling cardiac stem cells) induced formation of new EGFP-positive vessels and new EGFP-positive myocytes in a timedependent manner.10 This study was the first to propose that the newly formed myocytes from translocated cardiac stem cells possessed specific functional properties (such as higher shortening velocity) and contributed to improved cardiac performance and survival after MI. A study published earlier this year from the laboratory of Dr Houser in collaboration with Dr Anversa’s laboratory, reported that the properties of small myocytes present in the adolescent feline ventricle were distinct from the population of larger cells and also represent newly-formed myocytes.11 In the current issue Rota et al expand on the concept of the heart as an organ in continuous self-renewal.12 To do so, the authors have looked at markers for ‘age’ of myocytes of different sizes and have performed extensive functional characterization of myocytes of different sizes, this time in the heart of the mouse, at 3 months of age. Myocytes were subdivided according to volume. Small myocytes tended to be mononucleated, whereas larger myocytes had 2 or more nuclei. The majority, 91%, of the myocytes were binucleated. There was an inverse correlation between cell volume and telomere length suggesting loss of telomerase function in larger, old myocytes. On average, after classifying cells by volume, these larger myocytes also had a higher expression of p16, a marker of senescence.