Article

Cardiac cell therapy: Lessons from clinical trials

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Université Paris Descartes, INSERM U 633, Paris, France.
Journal of Molecular and Cellular Cardiology (Impact Factor: 5.22). 02/2011; 50(2):258-65. DOI: 10.1016/j.yjmcc.2010.06.010
Source: PubMed

ABSTRACT Cardiac cell therapy has now been in clinical use since 10 years. Both autologous skeletal myoblasts and bone marrow-derived different cell subsets (mononuclear cells, hematopoietic progenitors, mesenchymal stem cells) have been investigated in different settings (acute myocardial infarction, refractory angina and chronic heart failure). Despite the huge variability in cell processing techniques, dosing, timing of delivery and route for cell transfer, some lessons can yet be drawn, primarily from randomized controlled trials and summarized as follows: Techniques used for cell preparation are reasonably well controlled although better standardization and improvement in scale-up procedures remain necessary; cell therapy is overall safe, with the caveat of ventricular arrhythmias which still require careful scrutinization; the cell type needs to be tailored to the primary clinical indication, whereas the paracrine effects of bone marrow cells may be therapeutically efficacious for limitation of remodelling or relief of angina, only cells endowed with a true cardiomyogenic differentiation potential are likely to effect regeneration of chronic scars; autologous cells are primarily limited by their variable and unpredictable functionality, thereby calling attention to banked, consistent and readily available allogeneic cell products provided the immunological issues inherent in their use can be satisfactorily addressed; regardless of the cell type, a meaningful and sustained therapeutic benefit is unlikely to occur until cell transfer and survival techniques are improved to allow greater engraftment rates; and trial end points probably need to be reassessed to focus on mechanistic issues or hard end points depending on whether new or already extensively used cells are investigated. Hopefully, these lessons may serve as a building block whose incorporation in the design of second-generation trials will help making them more clinically successful. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

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    • "Studies have shown that cardiomyocytes treated with mesenchymal stem cells had prolonged action potential duration [14]. Similar to the in vitro data, in vivo studies have also suggested that transplanted bone marrow derived stem cells may also cause delays in electrical propagation, which may result in arrhythmia [10]. Finally, there has been an increasing interest in studying the potential of resident cardiac stem cells (CSCs) as therapeutic agents. "
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    ABSTRACT: Although stem cell therapy is promising for repairing damaged cardiac tissue and improving heart function, there are safety concerns, especially regarding the risk of arrhythmias, which can be life threatening. To address this issue, we propose to develop a novel screening system to evaluate arrhythmic risk associated with stem cell therapy using a high-throughput multielectrode array system that can measure conduction velocity and action potential duration in cardiomyocytes co-cultured with different types of stem cells, such as mesenchymal stem cells, skeletal myoblasts, and resident cardiac stem cells. We will assess the arrhythmic potential of each of these types of stem cells under normoxic and hypoxic conditions, with/without application of oxidative stress or catecholamines. We hypothesize that these methods will prove to be an effective way to screen for arrhythmic risk of cardiac stem cell therapy. Ultimately, our approach can potentially be personalized to develop a robust screening protocol in order to identify which stem cell type carries the least amount of risk for arrhythmia. This system will have great clinical benefit to improve the risk/benefit ratio of human stem cell therapy for heart disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Medical Hypotheses 01/2015; 84(4). DOI:10.1016/j.mehy.2015.01.015 · 1.07 Impact Factor
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    • "In general, many years of in vitro and in vivo experiments and clinical trials have permitted to draw some conclusions [39]. Cell therapy is overall safe, with the caveat of ventricular arrhythmias which still require careful scrutinization; the cell type needs to be tailored to the primary clinical indication, whereas the paracrine effects of bone marrow cells may be therapeutically efficacious for limitation of remodeling or relief of angina. "
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    ABSTRACT: Cardiovascular diseases represent the leading cause of death and disability in the world. At the end-stage of heart failure, heart transplantation remains the ultimate option. Therefore, due to the numerous drawbacks associated with this procedure, new alternative strategies to repair the wounded heart are required. Cell therapy is a potential option to regenerate functional myocardial tissue. The characteristics of the ideal cardiac cell therapy include the use of the proper cell type and delivery methods as well as the choice of a suitable biomaterial acting as a cellular vehicle. Since traditional delivery methods are characterized by several counter backs, among which low cell survival, new engineered micro-and nanostructured materials are today extensively studied to provide a good cardiac therapy. In this review, we report the most recent achievements in the field of cell therapy for myocardial infarction treatment and heart regeneration, focusing on the most commonly used cell sources, the traditional approaches used to deliver cells at the damaged site, and a series of novel technologies based on recent advancements of bioengineering, highlighting the tremendous potential that nanoscaffolds have in this framework.
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    • "Several clinical trials have been completed or are currently on the way investigating the use of hMSCs for the treatment of, amongst others, autoimmune diseases [2e5], myocardial infarcts [reviewed in Ref. [6]], solid organ/graft transplantations [7] [8] and ischemic wounds [9]. Debate exists on the mechanisms underlying the effects of infused MSCs. "
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    ABSTRACT: The repertoire of growth factors determines the biological engagement of human mesenchymal stromal cells (hMSCs) in processes such as immunomodulation and tissue repair. Hypoxia is a strong modulator of the secretome and well known stimuli to increase the secretion of pro-angiogenic molecules. In this manuscript, we employed a high throughput screening assay on an hMSCs cell line in order to identify small molecules that mimic hypoxia. Importantly, we show that the effect of these small molecules was cell type/species dependent, but we identified phenanthroline as a robust hit in several cell types. We show that phenanthroline induces high expression of hypoxia-target genes in hMSCs when compared with desferoxamine (DFO) (a known hypoxia mimic) and hypoxia incubator (2% O(2)). Interestingly, our microarray and proteomics analysis show that only phenanthroline induced high expression and secretion of another angiogenic cytokine, interleukin-8, suggesting that the mechanism of phenanthroline-induced hypoxia is distinct from DFO and hypoxia and involves the activation of other signaling pathways. We showed that phenanthroline alone was sufficient to induce blood vessel formation in a Matrigel plug assay in vivo paving the way to its application in ischeamic-related diseases.
    Biomaterials 01/2013; 34(12). DOI:10.1016/j.biomaterials.2012.12.037 · 8.31 Impact Factor
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