Menasche, P. Cardiac cell therapy: lessons from clinical trials. J Mol Cell Cardiol 50: 258-265

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: 4.66). 02/2011; 50(2):258-65. DOI: 10.1016/j.yjmcc.2010.06.010
Source: PubMed


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.
    Full-text · Article · Jan 2015 · Medical Hypotheses
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    • "Previous investigations revealed the sudden disappearance of cells administered by injection—systemically or locally—independent of cell type. This negative outcome has been ascribed to the low retention and high mortality of cells in the hypoxic environment characterized by an inflammatory response and the lack of local blood supply (Gnecchi et al., 2008; Menasche, 2011). The issue of promoting ischemic area vascularization has been lately addressed by cardiac tissue engineers through different approaches: (i) the administration of pro-angiogenic factors supplied by direct injection or through drug-releasing carriers (Sato et al., 2001; Chiu and Radisic, 2010; Singh et al., 2012); (ii) the infusion of endothelial progenitors (EPCs) or mature endothelial cells (ECs; Lian et al., 2008); and (iii) the pre-vascularization of the tissue constructs produced in vitro before implantation (Caspi et al., 2007; Dvir et al., 2009). "
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    ABSTRACT: The vascularization of tissue engineered products represents a key issue in regenerative medicine which needs to be addressed before the translation of these protocols to the bedside can be foreseen. Here we propose a multistep procedure to prepare pre-vascularized three-dimensional (3D) cardiac bio-substitutes using dynamic cell cultures and highly porous biocompatible gelatin scaffolds. The strategy adopted exploits the peculiar differentiation potential of two distinct subsets of adult stem cells to obtain human vascularized 3D cardiac tissues. In the first step of the procedure, human mesenchymal stem cells (hMSCs) are seeded onto gelatin scaffolds to provide interconnected vessel-like structures, while human cardiomyocyte progenitor cells (hCMPCs) are stimulated in vitro to obtain their commitment toward the cardiac phenotype. The use of a modular bioreactor allows the perfusion of the whole scaffold, providing superior performance in terms of cardiac tissue maturation and cell survival. Both the cell culture on natural-derived polymers and the continuous medium perfusion of the scaffold led to the formation of a densely packaged proto-tissue composed of vascular-like and cardiac-like cells, which might complete maturation process and interconnect with native tissue upon in vivo implantation. In conclusion, the data obtained through the approach here proposed highlight the importance to provide stem cells with complementary signals in vitro able to resemble the complexity of cardiac microenvironment.
    Full-text · Article · Jun 2014 · Frontiers in Physiology
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    • "Stem cells therapy has been identified as a promising approach to MI for their potentiality of differentiation into cardiomyocytes and ability of secretion growth factors and cytokines to nourish myocardium[2]. However, due to low cell engraftment and paracrine activity induced by tough cardiac microenvironment, mechanical injury and maladaptation, stem cells transplantation could only yield marginal benefits (3~4% left ventricular ejection fraction improvement), which severely restrict the clinical potential of this therapeutic approach[3-5]. Previous studies have clearly showed that physical stimulation[6], pharmacological agents treatment[7], genetic manipulation by over-expression of pro-survival related genes[8] could enhance differentiation potential and paracrine activity of stem cells. "
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    ABSTRACT: The therapeutic efficiency of bone marrow mononuclear cells (BMMNCs) autologous transplantation for myocardial infarction (MI) remains low. Here we developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation. Acute MI in rats led to a significant increase of AT2R expression in BMMNCs. Preconditioning of BMMNCs via AT2R stimulation directly with an AT2R agonist CGP42112A or indirectly with angiotensin II plus AT1R antagonist valsartan led to ERK activation and increased eNOS expression as well as subsequent nitric oxide generation, ultimately improved cardiomyocyte protection in vitro as measured by co-culture approach. Intramyocardial transplantation of BMMNCs preconditioned via AT2R stimulation improved survival of transplanted cells in ischemic region of heart tissue and reduced cardiomyocyte apoptosis and inflammation at 3 days after MI. At 4 weeks after transplantation, compared to DMEM and non-preconditioned BMMNCs group, AT2R stimulated BMMNCs group showed enhanced vessel density in peri-infarct region and attenuated infarct size, leading to global heart function improvement. Preconditioning of BMMNCs via AT2R stimulation exerts protective effect against MI. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair.
    Full-text · Article · Dec 2013 · PLoS ONE
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