Nature Clinical Practice. Cardiovascular Medicine最新文献

Recent preclinical and clinical studies have suggested that adult stem cells have the ability to promote the retention or restoration of cardiac function in acute and chronic ischemia. Published clinical studies have used autologous donor cells, including skeletal muscle myoblasts, cultured peripheral blood cells, or bone marrow cells. However, our research and that of others indicates that human adipose tissue is an alternative source of cells with potential for cardiac cell therapy. These findings include the presence of cells within adipose tissue that can differentiate into cells expressing a cardiomyocytic or endothelial phenotype, as well as angiogenic and antiapoptotic growth factors. This potential is supported by preclinical studies in large animals.

Although cardiac transplantation is still the treatment of choice for end-stage heart disease, the side effects derived from the use of immunosuppressants and the limited availability of donors have prompted the search for alternative therapeutic strategies. Among other possibilities, cell transplantation approaches have recently emerged as new alternatives to stimulate myocardial regeneration. These approaches are mainly based on the increasing number of reports documenting the plasticity of stem cells of various origins, particularly the ability of several types of embryonic and adult stem cells to give rise to cardiomyocytes. Unprecedented in the field of 'translational research' and based on the urgent need for alternative therapies, the promising results obtained with animal models have been quickly transferred to the clinical arena, where numerous small pilot studies using different cell types are already ongoing and/or have reported promising results. Nevertheless, the lack of randomization, the variability and small size of the treated cohorts and the use of mixed populations of cells have often clouded the significance and prevented a mechanistic interpretation of the results. Here, we briefly review the use of bone-marrow-derived and cardiac-derived stem/progenitor cells in myocardial regeneration studies and discuss their significance for the future of the field of myocardial regeneration.

Current treatments for myocardial infarction have significantly reduced the acute mortality of ischemic cardiomyopathy. This reduction has resulted in the survival of a large cohort of patients left with a significant 'myocyte deficit'. Once this deficit leads to heart failure there is no available therapy to improve long-term cardiac function. Recent developments in stem cell biology have focused on the possibility of regenerating contractile myocardial tissue. Most of these approaches have entailed the transplantation of exogenous cardiac-regenerating cells. Recently, we and others have reported that the adult mammalian myocardium, including that in humans, contains a small pool of cardiac stem and progenitor cells (CSCs) that can replenish the cardiomyocyte population and, in some cases, the coronary microcirculation. The human CSCs (hCSCs) are involved in maintaining myocardial cell homeostasis throughout life and participate in remodeling in cardiac pathology. They can be isolated, propagated and cloned. The progeny of a single cell clone differentiates in vitro and in vivo into myocytes, smooth muscle and endothelial cells. Surprisingly, in response to different forms of stress, hCSCs acquire a senescent, dysfunctional phenotype. Strikingly, these nonfunctional CSCs constitute around 50% of the total CSC pool in older individuals-those most likely to be candidates for hCSC-based myocardial regeneration. Therefore, the challenge to develop clinically effective therapies of myocardial regeneration is twofold: to produce the activation of the hCSCs in situ in order to obviate the need for cell transplantation, and to elucidate the mechanisms responsible for hCSC senescence in order to prevent or reverse its development.

Stem cell therapy after acute myocardial infarction is a promising therapeutic strategy. Intermediate-sized clinical trials to answer many unanswered questions must be carefully designed and surrogate end points carefully chosen. Moreover, imaging techniques accurate enough to measure surrogate parameters and to make it possible to reduce sample size are needed. The imaging technique of choice in this setting should be capable of tracking the destiny of the stem cells once injected in the heart and of quantifying left ventricular remodelling parameters. This information will be crucial in the design of multicenter, large, randomized trials to assess survival, which can definitively establish the usefulness of this therapeutic strategy.

After acute myocardial infarction, bone-marrow-derived cells (BMDCs) improve cardiac function; it is conceivable, but not yet demonstrated, that BMDC therapy might also be useful in chronic infarction. We treated 18 consecutive patients who had chronic myocardial infarction (between 5 months and 8.5 years postinfarction) using intracoronary transplantation of autologous BMDCs and compared this group with a representative control group who did not receive cell therapy. After 3 months, infarct size in the transplantation group was reduced by 30% and both global left ventricular ejection fraction and infarction wall-movement velocity were increased significantly (15% and 57%, respectively), whereas in the control group no significant changes were observed. After transplantation of BMDCs, there was an 11% improvement in maximum oxygen uptake and a 15% increase in regional (18)F-fluordeoxyglucose uptake into infarcted tissue, as determined by positron emission tomography. These results show that functional and metabolic regeneration of infarcted and chronically avital tissue can be achieved in humans using transplantation of bone-marrow-derived cells.