Nature Clinical Practice. Cardiovascular Medicine最新文献

Experimental data indicate that stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) might have potential as a novel therapeutic strategy for acute myocardial infarction. The prospective beneficial effects of G-CSF can be attributed mainly to a direct action on injured myocardium rather than on differentiation of mobilized bone marrow stem cells into cardiac myocytes. This article reviews the evidence for the potential cardioprotective effects of G-CSF and discusses future investigations regarding pharmacologic stem cell activation and mobilization with G-CSF in the setting of acute myocardial infarction.

Cardiovascular disease is the leading cause of death worldwide, which has encouraged the search for new therapies that enable the treatment of patients in palliative and curative ways. In the past decade, the potential benefit of transplantation of cells that are able to substitute for the injured tissue has been studied with several cell populations, such as stem cells. Some of these cell populations, such as myoblasts and bone marrow cells, are already being used in clinical trials. The laboratory of CM Verfaillie has studied primitive progenitors, termed multipotent adult progenitor cells, which can be isolated from adult bone marrow. These cells can differentiate in vitro at the single-cell level into functional cells that belong to the three germ layers and contribute to most, if not all, somatic cell types after blastocyst injection. This remarkably broad differentiation potential makes this particular cell population a candidate for transplantation in tissues in need of regeneration. Here, we focus on the regenerative capacity of multipotent adult progenitor cells in several ischemic mouse models, such as acute and chronic myocardial infarction and limb ischemia.

Intramyocardial delivery of genes and cells derived from bone marrow has been evaluated in several small studies of 'no-option' symptomatic patients with chronic ischemic coronary artery disease. Clinical experience with intramyocardial gene delivery is limited to genes encoding isoforms of vascular endothelial cell growth factor. In the largest study (Euroinject One), 80 patients were randomized to receive a plasmid encoding vascular endothelial cell growth factor 165 or placebo. The results of this study suggested no beneficial therapeutic effect of this strategy. The experience with stem cells is limited to use of autologous, nonexpanded, nonmanipulated bone-marrow-derived cells; thus, the number of injected stem cells reflects their natural proportion within the bone marrow. The results of these preliminary studies suggest this approach is feasible and has a high safety profile. Although no conclusion can yet be made regarding efficacy, the improved myocardial perfusion in all four studies described in this Review is encouraging. Data from assessments of individual patients, however, suggests a wide variability in response, underscoring the need for further bench and clinical investigations.

The first human trial of stem cell therapy for cardiovascular disease was performed 4 years ago. Since that time, almost a dozen studies have reported the early and late clinical effects of cell therapy in acute myocardial infarction and chronic ischemic cardiomyopathy. Initial nonrandomized trials universally showed slight improvement in the left ventricular ejection fraction. Later randomized, controlled trials, however, suggested a less significant effect. They showed either no difference between cell therapy and control treatment or a slight treatment benefit with cell therapy that is lost by 12 months' follow-up. These results have dampened the enthusiasm of some members of the scientific community for the continuation of clinical trials. Because early phase I trials should not be judged on issues other than safety, however, research is unlikely to be hindered. Indeed, the clinical studies reported so far have already taught us a lot about the biology of myocardial repair. Achieving clinical success will, however, probably require much more investment in basic and experimental research. Here, we address some of the current pitfalls in clinical cell therapy trials and lessons that should be learned as we face the challenges of the future.

Clinical and basic studies of cell-based myocardial therapy have proceeded at a rapid pace. Cell therapy could lead to successful cardiac regeneration or repair by any of three general mechanisms: differentiation of the administered cells into all of the cellular constituents of the heart; release of factors capable of paracrine signaling from the administered cells; and fusion of the administered cells with the existing constituents of the heart. Here, we argue that a fourth general mechanism could be operative: stimulation of endogenous repair by injected cells, which and might cause the regeneration of stem cell niches. In a porcine model of myocardial infarction, allogeneic mesenchymal stem cells stimulated substantial improvement in the ejection fraction, reduction of infarct size, and the growth of a rim of new cardiac tissue in the region in which the mesenchymal stem cells were injected. These effects occurred in the absence of definitive cardiac myocyte differentiation. After myocardial infarction, porcine hearts exhibit evidence of cardiac myocytes that have entered the cell cycle, neovascularization, and reduced levels of apoptosis. These data, in addition to new insights regarding the presence of endogenous cardiac stem cells, strongly support the concept that the heart could contain stem cell niches. Effective cell therapy could lead to restoration of these niches through multifaceted cell-cell interactions.

Cell therapy is a promising option for the treatment of ischemic diseases. Infusion or injection of stem or progenitor cells has improved neovascularization and heart function after ischemia in various experimental studies and clinical phase II and III trials. One potential limitation for cell therapy is a low rate of engraftment and persistence of cells in the ischemic tissue. Moreover, impairment of the number and function of patient-derived progenitor cells might limit the efficiency of autologous stem cell therapy. Therefore, strategies to augment cell function, survival, and homing could be crucial to improve success rates for cell therapy. Experimental studies have provided novel options for improving survival and function by transduction of stem or progenitor cells with prosurvival genes (e.g. Akt or telomerase). Pretreatment of cells with small molecules, such as statins, p38 inhibitors, or endothelial nitric oxide synthase enhancers, has been used to augment cell homing, integration, and functional recovery after induction of ischemia. Priming of the tissue by mechanical activation or application of growth factors might further improve recruitment and incorporation of cells. In this article we summarize the experimental studies providing novel concepts for cell-enhancement strategies to aid the treatment of peripheral artery occlusive and ischemic heart disease.

Granulocyte-colony-stimulating factor (G-CSF) seems to have direct cardioprotective effects related to mobilization of autologous bone-marrow mononuclear CD34(+) cells. These properties have attracted the attention of researchers investigating new therapeutic strategies for acute myocardial infarction. The role of G-CSF in bone-marrow cell mobilization removes the need for bone-marrow aspiration and repeated invasive procedures. This factor, coupled with the fact that G-CSF can be administered by noninvasive subcutaneous injection, give this approach a potential advantage over other cell-therapy options. This article is intended to present a concise overview of the current experimental and clinical findings for G-CSF therapy after acute myocardial infarction. In particular, we discuss the conflicting findings from the front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction (FIRSTLINE-AMI) and the Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL-2) studies.

Initial clinical trials of bone-marrow-derived mononuclear cells after acute myocardial infarction have shown improvement in a number of cardiac indices, including left ventricular systolic function, infarct size, stroke volume, and coronary blood flow. Functional improvements observed in cell therapy studies have been modest, with augmentation of left ventricular function in the range of 6-8%. Nevertheless, these studies have generated considerable debate on a number of issues, including the efficacy of specific cell populations, logistics of cell harvesting and isolation, and, most importantly, the mechanism of cell therapy benefit. With the field on the threshold of large-scale, randomized, controlled clinical trials, additional questions, such as the following, must be asked. Can cell therapy procedures be simplified? Can therapeutic effects be obtained earlier after myocardial infarction? Is cell harvesting a necessary component of cell therapy or can endogenous cells be mobilized sufficiently to obviate the need for processing exogenous cells? In an era when interventional devices are increasingly used in therapeutic approaches to acute myocardial infarction, can current cell therapy practice be integrated with interventional approaches to acute revascularization? Emerging concepts that may address some of these questions include whether paracrine factors released by progenitor or stem cells can be as efficacious as bone-marrow- or blood-derived cells, whether novel progenitor populations mobilized locally in the vessel wall or the heart can participate in repair or regeneration, and whether cell therapy strategies for acute myocardial infarction will evolve to include interventional technologies in combination with paracrine or mobilization factors.

The possibility that cardiac cell-repair therapy might become a clinical reality is a challenge worthy of the current state of technological and scientific expertise at the start of the 21(st) century. The success of preclinical and early clinical studies is a strong inducement to move ahead with larger clinical trials, but caution is warranted given our lack of understanding of the potential mechanisms by which cell-repair therapy exerts a benefit on ventricular function, perfusion, and infarct size, irrespective of the type of cell, method, site, and disease entity. There are multiple clinical, mechanistic, and safety questions requiring answers, and these will be forthcoming only if the design of clinical trials is carefully tailored to answer specific questions. These questions, in turn, will require the use of different and multiple end points, depending on the specific issue and study. Accordingly, this review addresses the limitations of current clinical studies, the design of future trials, and the concept of a hierarchical series of end points that might provide answers to a host of different questions. Clinical and basic scientists need to approach the next generation of trials in partnership.

Embryonic stem cells (ESCs) can be propagated indefinitely in culture, while retaining the ability to differentiate into any cell type in the organism. The molecular and cellular mechanisms underlying ESC pluripotency are, however, poorly understood. We characterize a population of early mesoderm-specified (EM) progenitors that is generated from mouse ESCs by bone morphogenetic protein stimulation. We further show that pluripotent ESCs are actively regenerated from EM progenitors by the action of the divergent homeodomain-containing protein Nanog, which, in turn, is upregulated in EM progenitors by the combined action of leukemia inhibitory factor and the early mesoderm transcription factor T/Brachyury. These findings uncover specific roles of leukemia inhibitory factor, Nanog, and bone morphogenetic protein in the self-renewal of ESCs and provide novel insights into the cellular bases of ESC pluripotency.