br Introduction Despite the remarkable progress
Introduction Despite the remarkable progress made during the past half century in the treatment of cardiovascular disease, which is increasingly effective in dealing with the acute stages of life-threatening pathology, they often extend the life of the patient at the expense of generating a chronic condition. The chronic sequels from an acute myocardial infarction (AMI), such as chronic heart failure (CHF), are frequently without effective treatment or leave organ transplantation as the only alternative to restore function, with all the logistic, economic and biological limitations associated with this intervention (Kahan et al., 2011). The continuous increase in average human lifespan with progressive aging of the population in all developed countries has generated an increasingly severe epidemic of chronic diseases whose treatment absorbs an ever-larger fraction of human resources and of the healthcare budget. Presently, there are >5million patients in CHF post-AMI in the USA alone (Roger et al., 2012). More than 550,000 new patients per year are added to this group, which has a similar prevalence in the EU countries. After the first episode, CHF post-AMI has an average annual mortality rate of ~18% and in the USA alone absorbs >$30billion annually for its care (Roger et al., 2012). The root problem of CHF in general and post-AMI in particular is a deficit of functional myocardial contractile SW033291 (cardiomyocytes) and adequate coronary circulation to nurture them. This combination triggers pathological cardiac remodelling, which, in turn, produces further myocyte death and the late development of cardiac failure in these patients (Jessup et al., 2003). For these reasons, during the past decade a goal of cardiovascular research has been to find methods to replace the cardiomyocytes lost as a consequence of an MI and other insults in order to prevent or reverse the pathological cardiac remodelling. Therefore, stem cell-based therapies have become an attractive experimental treatment for heart disease and failure (Terzic et al., 2010).
The adult heart is a self-renewing organ Over the past 15years there has been a slow but steady re-evaluation of the prevalent paradigm about adult mammalian – including human – tissue cellular homeostasis. It has been slowly appreciated that the parenchymal cell population of most, if not all, adult tissues is in a continuous process of self-renewal with cells continuously dying and new ones being born. Once cell turnover was accepted as a widespread phenomenon in the adult organs, it was rapidly surmised that in order to preserve tissue mass, each organ constituted mainly of terminally differentiated cells needed to have a population of tissue-specific regenerating cells. Not surprisingly, this realization was rapidly followed by the progressive identification of stem cells in each of the adult body tissues, even including the brain (Rountree et al., 2012; Reule et al., 2011; Kopp et al., 2011; Kotton, 2012; Buckingham et al., 2008; Suh et al., 2009). Despite the change in the concept of tissue cell homeostasis, the cardiovascular research community has continued to treat the adult mammalian heart as a post-mitotic organ without intrinsic regenerative capacity. Notwithstanding several reports showing a yet contradictory range from 0.0005% to 3% cardiomyocyte cell cycle activity in normal adult mammalian hearts (Rumyantsev, 1991: 3; Soonpaa et al., 1998; Anversa and Kajstura, 1998), the prevalent view considered the 0.0005% as the most appropriate estimate for cardiomyocyte renewal, establishing in essence its negligent value. The >20-fold increase in cardiac mass from birth to adulthood and in response to different stimuli, was believed to result exclusively from the enlargement of pre-existing myocytes (Hunter et al., 1999; Soonpaa et al., 1998; Laflamme at al., 2011). It was accepted that this myocyte hypertrophy, in turn, was uniquely responsible for the initial physiological adaptation and subsequent deterioration of the overloaded heart. This belief has been based on two generally accepted but erroneous notions: a) all myocytes in the adult heart were formed during foetal life or shortly thereafter, became terminally differentiated and could not be recalled into the cell cycle: therefore, all cardiac myocytes have to be of the same chronological age as the individual (Oh et al., 2001; Chien et al., 2002); b) the heart has no intrinsic parenchymal regenerative capacity because it lacks a stem/progenitor cell population able to generate new myocytes. These concepts were extrapolated into the dogma that from shortly after birth until death no new CM generation was possible and any CMs lost by either wear and tear or injury were not replaced. Thus, from puberty on the myocardium entered an irreversible downslope with a continuously decreasing number of myocytes. This continuous loss was thought to be compensated for some time by hypertrophy of the spared CMs which managed to maintain myocardial mass. In this world there was neither room nor need for endogenous regenerative cardiac biology. Therefore, in the terminally differentiated heart, regeneration could only be accomplished by the replacement of the lost or damaged cardiomyocytes through transplantation of exogenous differentiated CMs or with cells with the potential to differentiate into them.