Mixed Results for Bone Marrow–Derived Cell Therapy for Ischemic Heart Disease

Marbán, Eduardo; Malliaras, Konstantinos

doi:10.1001/jama.2012.64751

Cited by 41 publications

(29 citation statements)

References 17 publications

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“…1, 27 Many of the clinical trials (FOCUS, TIME, Late-Time) recently performed by the NIH-sponsored Cardiovascular Cell Therapy Research Network have used BMMCs. 27, 28 The results of our study, however, suggest that BMMCs may not be the optimal cell to regenerate new myocardium. Only 1 mouse injected with BMMCs showed evidence of accelerated healing and myocardial regeneration.…”

Section: Discussionmentioning

confidence: 99%

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Microstructural Impact of Ischemia and Bone Marrow–Derived Cell Therapy Revealed With Diffusion Tensor Magnetic Resonance Imaging Tractography of the Heart In Vivo

et al. 2014

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Background The arrangement of myofibers in the heart is highly complex and must be replicated by injected cells to produce functional myocardium. A novel approach to characterize the microstructural response of the myocardium to ischemia and cell therapy, using serial diffusion tensor MRI (DTI) tractography of the heart in vivo, is presented. Methods and Results Validation of the approach was performed in normal (n=6) and infarcted mice (n=6) as well as healthy human volunteers. Mice (n=12) were then injected with bone marrow mononuclear cells (BMMCs) 3 weeks after coronary ligation. In half the mice the donor and recipient strains were identical and in half the strains were different. A positive response to cell injection was defined by a decrease in mean diffusivity, an increase in fractional anisotropy, and the appearance of new myofiber tracts with the correct orientation. A positive response to BMMC injection was seen in one mouse. The response of the majority of mice to BMMC injection was neutral (9/12) or negative (2/12). The in vivo tractography findings were confirmed with histology. Conclusions DTI-tractography was able to directly resolve the ability of injected cells to generate new myofiber tracts and provided a fundamental readout of their regenerative capacity. A highly novel and translatable approach to assess the efficacy of cell therapy in the heart is thus presented.

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Section: Discussionmentioning

confidence: 99%

“…These data are consistent with the results of the TIME, Late-Time and FOCUS trials, in which the injection of BMMCs showed no benefit. 27, 28 DTI-tractography may thus provide a uniquely powerful tool to assess the efficacy of novel stem/progenitor cells in preclinical models and subsequently in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Microstructural Impact of Ischemia and Bone Marrow–Derived Cell Therapy Revealed With Diffusion Tensor Magnetic Resonance Imaging Tractography of the Heart In Vivo

et al. 2014

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“…Importantly, manufacturing details can influence the potency of BMMCs. This may explain why, though their safety record has proven superior, intracoronary BMMC trial results have been so variable (110,111). The lack of excess arrhythmias in BMMC-treated patients (unlike earlier experience with skeletal myoblasts) is particularly notable (106).…”

Section: Cell Therapy For Heart Disease: a Glass Half Fullmentioning

confidence: 99%

Translating Stem Cell Research to Cardiac Disease Therapies

Rosen

Myerburg

Francis

et al. 2014

Journal of the American College of Cardiology

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Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of articles focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies. The first section by Rosen and Myerburg is an independent review that analyzes the basic science and translational strategies supporting the rapid advance of stem cell technology to the clinic, the philosophies behind them, trial designs, and means for going forward that may impact favorably on progress. The second and third sections were collected in response to the initial section of this review. The commentary by Francis and Cole discusses the Rosen and Myerburg review and details how trial outcomes can be affected by noise, poor trial design (particularly the absence of blinding), and normal human tendencies toward optimism and denial. The final, independent article by Marbán takes a different perspective concerning the potential for positive impact of stem cell research applied to heart disease and future prospects for its clinical application.

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“…[62,63] The CCTRN-trials have been performed using an automated cell-sorting system for the isolation of BM-MNCs. [64,65] However, whether these cells are efficient in an experimental myocardial infarction model in vivo has not been reported. Therefore, as isolation procedure steps may have a crucial influence on cell functionality, the functional properties of these cells after automatic separation may be a determinant for the in vivo effects.…”

Section: Potential Impact Of Cell Isolation Procedures and Impaired Fmentioning

confidence: 99%

Current Status of Cell-Based Therapy for Heart Failure

Jakob

Landmesser

2013

Curr Heart Fail Rep

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In the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies. However, despite these advances, there is a substantial unmet need for novel therapies, ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults. In this respect, cardiac cell-based therapies have gained substantial attention and have entered clinical feasibility and safety studies a decade ago. Different cell-types have been used, including bone marrow-derived mononuclear cells, bone marrow-derived mesenchymal stem cells, mobilized CD34+ cells, and more recently cardiac-derived c-kit+ stem cells and cardiosphere-derived cells. Some of these studies have suggested a potential of cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. While first clinical trials examining the impact of cardiac cell-based therapy on clinical outcome have now been initiated, improved understanding of underlying mechanisms of action of cell-based therapies may lead to strategies for optimization of the cardiac repair potential of the applied cells. In experimental studies, direct in vivo reprogramming of cardiac fibroblasts towards cardiomyocytes, and microRNA-based promotion of cardiomyocyte proliferation and cardiac repair have recently been reported that may represent novel therapeutic approaches for cardiac regeneration that would not need cell-administration but rather directly stimulate endogenous cardiac regeneration. This review will focus mainly on recently completed clinical trials (within the last 2 years) investigating cardiac cell-based therapies and the current status of experimental studies for cardiac cell-based repair and regeneration with a potential for later translation into clinical studies in the future. AbstractIn the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies.However, despite these advances, there is a substantial unmet need for novel therapies ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults.In this respect, cardiac cell-based therapies have gained substantial attention and

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Mixed Results for Bone Marrow–Derived Cell Therapy for Ischemic Heart Disease

Cited by 41 publications

References 17 publications

Microstructural Impact of Ischemia and Bone Marrow–Derived Cell Therapy Revealed With Diffusion Tensor Magnetic Resonance Imaging Tractography of the Heart In Vivo

Microstructural Impact of Ischemia and Bone Marrow–Derived Cell Therapy Revealed With Diffusion Tensor Magnetic Resonance Imaging Tractography of the Heart In Vivo

Translating Stem Cell Research to Cardiac Disease Therapies

Current Status of Cell-Based Therapy for Heart Failure

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