Generation of new cardiomyocytes in the adult heart: Prospects of myocardial regeneration as an alternative to cardiac transplantation

The classic dogma, still prevalent in cardiology, that the adult myocardium is a terminally differentiated tissue unable to produce new cardiomyocytes needs to be revised in light of recent results. in human and experimental animals there is now incontrovertible evidence that new myocytes are contin uously generated throughout life in response to physiological and pathologi cal stimuli. Moreover, the elucidation of mechanisms responsible for the hy pertrophic response indicate similarity and overlap with the mechanisms inv olved in cell death by apoptosis as well as cell growth. During cardiac development, from birth to adulthood, there is a balance bet ween the stimuli induce cell growth -by hypertrophy and hyperplasia- on one hand and those that induce programmed cell death on the other. In human an d experimental animals it has been well documented that pathological condit ions, such as diabetes and hypertension, can increase dramatically the rate of cell death. Moreover, high rates of cell death have been measured in no rmal adult human hearts and those of mice and rats. No surprisingly, these values increase significantly with age and high in senescence. By themselve s, these high rates of normal cell death provide a very compelling argument in favor of cardiomyocyte regeneration. Without cell renewal, these rates of cell death would be incompatible with survival because the heart would d isappear before early adulthood. As expected, direct measurement of rates o f new cell formation in adult hearts demonstrate high rates of cell renewal that compensate for cell death. Thus, the heart is in continuous cellular turnover with new myocardial cells replacing the older ones. Experiments with fetal mouse cardiocytes shows that the retinoblastoma prot ein is responsible for the cardiocyte withdrawal from the cell cycle during development. The identification in the adult heart of a subpopulation of q uiescent cells that have many of the characteristics of stem cells able to rapidly enter the cell cycle and generate new cardiocytes is yet another ev idence that the heart continuously produces new cardiocytes to replace thos e that disappear either by apoptosis or necrosis. Surprisingly, stem cells other that those from the heart are able to produc e new cardiocytes and repopulate the myocardium. We have used bone marrow s tem cells injected into the border zone of post-coronary occlusion necrosis . Remarkably, these cells have proven to be very effective in generating ne w myocardium in the necrotic zone that is integrated to the rest of the mus cle and irrigated by new vessels. These results demonstrate that stem cells provide a new avenue for the generation of new contractile tissue. This ap proach could prove useful in the treatment of chronic cardiac failure and p ost-ischemic necrosis.