Current Status of Stem Cell Therapy in Heart Failure

Codina, Marta; Elser, Jeremy; Margulies, Kenneth B.

doi:10.1007/s11886-010-0098-5

Cited by 19 publications

(17 citation statements)

References 48 publications

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“…It is still uncertain, for example, how inflammatory and oxidative processes affect the selfregenerative potential of the cardiac muscle; to what extent the paracrine beneficial effects of resident or autologous stem cells are altered by the imbalanced redox environment; and whether current therapies beneficially or detrimentally influence cardiac regenerative strategies (83,213). On-going preclinical and medium-sized clinical studies could help to answer some of these questions (86).…”

Section: Therapeutic Opportunities For Hfmentioning

confidence: 99%

Nitric Oxide/Reactive Oxygen Species Generation and Nitroso/Redox Imbalance in Heart Failure: From Molecular Mechanisms to Therapeutic Implications

Nediani

Raimondi

Borchi

et al. 2011

Antioxidants & Redox Signaling

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Adaptation of the heart to intrinsic and external stress involves complex modifications at the molecular and cellular levels that lead to tissue remodeling, functional and metabolic alterations, and finally to failure depending upon the nature, intensity, and chronicity of the stress. Reactive oxygen species (ROS) have long been considered as merely harmful entities, but their role as second messengers has gradually emerged. At the same time, our comprehension of the multifaceted role of nitric oxide (NO) and the related reactive nitrogen species (RNS) has been upgraded. The tight interlay between ROS and RNS suggests that their imbalance may implicate the impairment in physiological NO/redox-based signaling that contributes to the failing of the cardiovascular system. This review initially provides basic concepts on the role of nitroso/oxidative stress in the pathophysiology of heart failure with a particular focus on sources of ROS/RNS, their downstream targets, and endogenous modulators. Then, the role of NO/redox regulation of cardiomyocyte function, including calcium homeostasis, electrogenesis, and insulin signaling pathways, is described. Finally, an overview of old and emerging therapeutic opportunities in heart failure is presented, focusing on modulation of NO/redox mechanisms and discussing benefits and limitations.

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Section: Therapeutic Opportunities For Hfmentioning

confidence: 99%

Nitric Oxide/Reactive Oxygen Species Generation and Nitroso/Redox Imbalance in Heart Failure: From Molecular Mechanisms to Therapeutic Implications

Nediani

Raimondi

Borchi

et al. 2011

Antioxidants & Redox Signaling

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“…Much attention has been directed toward the potential clinical application of these cells in the context of regenerative medicine and cell-based therapy [for reviews, see (Codina et al, 2010; Habib et al, 2008; Laflamme et al, 2007b; Li et al, 2009)]. Despite early successes with basic science studies and experimentation using animal hearts, clinical studies in general have not yet met with similar success (Lovell and Mathur, 2010).…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological and contractile function of cardiomyocytes derived from human embryonic stem cells

Blazeski

Zhu

Hunter

et al. 2012

Progress in Biophysics and Molecular Biology

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Human embryonic stem cells have emerged as the prototypical source from which cardiomyocytes can be derived for use in drug discovery and cell therapy. However, such applications require that these cardiomyocytes (hESC-CMs) faithfully recapitulate the physiology of adult cells, especially in relation to their electrophysiological and contractile function. We review what is known about the electrophysiology of hESC-CMs in terms of beating rate, action potential characteristics, ionic currents, and cellular coupling as well as their contractility in terms of calcium cycling and contraction. We also discuss the heterogeneity in cellular phenotypes that arises from variability in cardiac differentiation, maturation, and culture conditions, and summarize present strategies that have been implemented to reduce this heterogeneity. Finally, we present original electrophysiological data from optical maps of hESC-CM clusters.

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“…In some studies, direct delivery of filtered, autologous bone marrow cells (BMCs) into the coronary arteries or myocardial wall resulted in statistically-significant increases in cardiac performance, but these improvements were also inadequate to improve survival. Low engraftment rates were cited as a primary limitation in some of these studies [5]. Indeed, follow-up studies determined that 93–98% of bone marrow cells delivered via coronary artery fail to engraft and cannot be detected in the heart within 1 hour [6][7].…”

Section: Introductionmentioning

confidence: 99%

Ischemia induces P-selectin-mediated selective progenitor cell engraftment in the isolated-perfused heart

Elser

Purcell

Allana

et al. 2012

Journal of Molecular and Cellular Cardiology

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Rationale-Clinical trials infusing Bone Marrow Cells (BMCs) into injured hearts have produced measureable improvements in cardiac performance, but were insufficient to improve patient outcomes. Low engraftment rates are cited as probable contributor to limited improvements.Objective-To understand the mechanisms that control myocardial engraftment of BMCs following ischemia-reperfusion injury.Methods and Results-In isolated-perfused mouse hearts, stop-flow ischemia was followed by variable-duration reperfusion (0-60 min) before addition of labeled syngenic BMCs to the perfusate. After a buffer-only wash, the heart was disaggregated. Retained BMCs (digest) and infused BMCs (aliquot) were compared by flow cytometry for c-kit and CD45 expression to determine the proportion of cell subtypes engrafted versus delivered (selectivity ratio). In these studies, a time-dependent selective retention of c-kit+ cells was apparent starting at 30 minutes of reperfusion, at which time c-kit+/CD45+ BMCs showed a selectivity ratio of 18±2 (versus 2±1 in sham-ischemic controls). To study the underlying mechanism for this selective retention, neutralizing antibodies for P-selectin or L-selectin were infused into the heart preparation and incubated with BMCs prior to BMC infusion. Blocking P-selectin in ischemic hearts ablated selectivity for c-kit+/CD45+ BMCs at 30 min reperfusion (selectivity ratio of 3±1) while selectivity persisted in the presence of L-selectin neutralization (selectivity ratio of 17±2). To corroborate this finding, a parallel plate flow chamber was used to study capture and rolling dynamics of purified c-kit+ versus c-kit− BMCs on various selectin molecules. C-kit+ BMCs interacted weakly with L-selectin substrates (0.03±0.01% adhered) but adhered strongly to Pselectin (0.28±0.04% adhered). C-kit− BMCs showed intermediate binding regardless of substrate (0.18±0.04% adhered on L-selectin versus 0.17±0.04% adhered on P-selectin).Conclusions-Myocardial ischemia-reperfusion stress induces selective engraftment of c-kit+ bone marrow progenitor cells via P-selectin activation.

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Current Status of Stem Cell Therapy in Heart Failure

Cited by 19 publications

References 48 publications

Nitric Oxide/Reactive Oxygen Species Generation and Nitroso/Redox Imbalance in Heart Failure: From Molecular Mechanisms to Therapeutic Implications

Nitric Oxide/Reactive Oxygen Species Generation and Nitroso/Redox Imbalance in Heart Failure: From Molecular Mechanisms to Therapeutic Implications

Electrophysiological and contractile function of cardiomyocytes derived from human embryonic stem cells

Ischemia induces P-selectin-mediated selective progenitor cell engraftment in the isolated-perfused heart

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