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      Cardiac regeneration and diabetes

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      Regenerative Medicine Research
      Springer Nature

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          Abstract

          The prevalence of diabetes continues to increase world-wide and is a leading cause of morbidity, mortality, and rapidly rising health care costs. Although strict glucose control combined with good pharmacological and non-pharmacologic interventions can increase diabetic patient life span, the frequency and mortality of myocardial ischemia and infarction remain drastically increased in diabetic patients. Therefore, more effective therapeutic approaches are urgently needed. Over the past 15 years, cellular repair of the injured adult heart has become the focus of a rapidly expanding broad spectrum of pre-clinical and clinical research. Recent clinical trials have achieved favorable initial endpoints with improvements in cardiac function and clinical symptoms following cellular therapy. Due to the increased risk of cardiac disease, cardiac regeneration may be one strategy to treat patients with diabetic cardiomyopathy and/or myocardial infarction. However, pre-clinical studies suggest that the diabetic myocardium may not be a favorable environment for the transplantation and survival of stem cells due to altered kinetics in cellular homing, survival, and in situ remodeling. Therefore, unique conditions in the diabetic myocardium will require novel solutions in order to increase the efficiency of cellular repair following ischemia and/or infarction. This review briefly summarizes some of the recent advances in cardiac regeneration in non-diabetic conditions and then provides an overview of some of the issues related to diabetes that must be addressed in the coming years.

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          Most cited references71

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          Adult cardiac stem cells are multipotent and support myocardial regeneration.

          The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing approximately 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.
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            Mobilized bone marrow cells repair the infarcted heart, improving function and survival.

            Attempts to repair myocardial infarcts by transplanting cardiomyocytes or skeletal myoblasts have failed to reconstitute healthy myocardium and coronary vessels integrated structurally and functionally with the remaining viable portion of the ventricular wall. The recently discovered growth and transdifferentiation potential of primitive bone marrow cells (BMC) prompted us, in an earlier study, to inject in the border zone of acute infarcts Lin(-) c-kit(POS) BMC from syngeneic animals. These BMC differentiated into myocytes and vascular structures, ameliorating the function of the infarcted heart. Two critical determinants seem to be required for the transdifferentiation of primitive BMC: tissue damage and a high level of pluripotent cells. On this basis, we hypothesized here that BMC, mobilized by stem cell factor and granulocyte-colony stimulating factor, would home to the infarcted region, replicate, differentiate, and ultimately promote myocardial repair. We report that, in the presence of an acute myocardial infarct, cytokine-mediated translocation of BMC resulted in a significant degree of tissue regeneration 27 days later. Cytokine-induced cardiac repair decreased mortality by 68%, infarct size by 40%, cavitary dilation by 26%, and diastolic stress by 70%. Ejection fraction progressively increased and hemodynamics significantly improved as a consequence of the formation of 15 x 10(6) new myocytes with arterioles and capillaries connected with the circulation of the unaffected ventricle. In conclusion, mobilization of primitive BMC by cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of ischemic heart disease and, perhaps, other forms of cardiac pathology.
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              Human cardiac stem cells.

              The identification of cardiac progenitor cells in mammals raises the possibility that the human heart contains a population of stem cells capable of generating cardiomyocytes and coronary vessels. The characterization of human cardiac stem cells (hCSCs) would have important clinical implications for the management of the failing heart. We have established the conditions for the isolation and expansion of c-kit-positive hCSCs from small samples of myocardium. Additionally, we have tested whether these cells have the ability to form functionally competent human myocardium after infarction in immunocompromised animals. Here, we report the identification in vitro of a class of human c-kit-positive cardiac cells that possess the fundamental properties of stem cells: they are self-renewing, clonogenic, and multipotent. hCSCs differentiate predominantly into cardiomyocytes and, to a lesser extent, into smooth muscle cells and endothelial cells. When locally injected in the infarcted myocardium of immunodeficient mice and immunosuppressed rats, hCSCs generate a chimeric heart, which contains human myocardium composed of myocytes, coronary resistance arterioles, and capillaries. The human myocardium is structurally and functionally integrated with the rodent myocardium and contributes to the performance of the infarcted heart. Differentiated human cardiac cells possess only one set of human sex chromosomes excluding cell fusion. The lack of cell fusion was confirmed by the Cre-lox strategy. Thus, hCSCs can be isolated and expanded in vitro for subsequent autologous regeneration of dead myocardium in patients affected by heart failure of ischemic and nonischemic origin.
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                Author and article information

                Journal
                Regenerative Medicine Research
                Regen Med Res
                Springer Nature
                2050-490X
                2014
                2014
                : 2
                : 1
                : 1
                Article
                10.1186/2050-490X-2-1
                4f9fd316-a973-43ea-ad3d-a929991a88ce
                © 2014

                This work is licensed under a Creative Commons Attribution 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History

                Medicine,Surgery
                Medicine, Surgery

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