Electrophysiological Challenges of Cell-Based Myocardial Repair

Chen, Huei‐Sheng Vincent; Kim, Changsung; Mercola, Mark

doi:10.1161/circulationaha.107.751412

Cited by 98 publications

(87 citation statements)

References 121 publications

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“…npg is one of the major hurdles for the application of hESCs to cardiac repair [1,5,6]. The application of relatively homogeneous ventricular myocytes derived from hESCs in myocardial repair has a great potential to reduce this risk by removing one of the major barriers for developing hESC-based myocardial repair strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Swine transplantation studies have shown that implanted hESC-derived cardiomyocytes have pace-making activities, which are a potential cause of ventricular arrhythmias [5]. The application of hESCs in myocardial repair is hampered by this cardiac subtype heterogeneity of hESC-derived cardiomyocytes [6]. To direct the differentiation of hESCs into a desired cardiac subtype, the mechanisms of cardiac subtype specification must be uncovered.…”

Section: Introductionmentioning

confidence: 99%

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Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

et al. 2010

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Although myocyte cell transplantation studies have suggested a promising therapeutic potential for myocardial infarction, a major obstacle to the development of clinical therapies for myocardial repair is the difficulties associated with obtaining relatively homogeneous ventricular myocytes for transplantation. Human embryonic stem cells (hESCs) are a promising source of cardiomyocytes. Here we report that retinoid signaling regulates the fate specification of atrial versus ventricular myocytes during cardiac differentiation of hESCs. We found that both Noggin and the panretinoic acid receptor antagonist BMS-189453 (RAi) significantly increased the cardiac differentiation efficiency of hESCs. To investigate retinoid functions, we compared Noggin+RAi-treated cultures with Noggin+RA-treated cultures. Our results showed that the expression levels of the ventricular-specific gene IRX-4 were radically elevated in Noggin+RAi-treated cultures. MLC-2V, another ventricular-specific marker, was expressed in the majority of the cardiomyocytes in Noggin+RAi-treated cultures, but not in the cardiomyocytes of Noggin+RA-treated cultures. Flow cytometry analysis and electrophysiological studies indicated that with 64.7 ± 0.88% (mean ± s.e.m) cardiac differentiation efficiency, 83% of the cardiomyocytes in Noggin+RAi-treated cultures had embryonic ventricular-like action potentials (APs). With 50.7 ± 1.76% cardiac differentiation efficiency, 94% of the cardiomyocytes in Noggin+RA-treated cultures had embryonic atrial-like APs. These results were further confirmed by imaging studies that assessed the patterns and properties of the Ca 2+ sparks of the cardiomyocytes from the two cultures. These findings demonstrate that retinoid signaling specifies the atrial versus ventricular differentiation of hESCs. This study also shows that relatively homogeneous embryonic atrial-and ventricular-like myocyte populations can be efficiently derived from hESCs by specifically regulating Noggin and retinoid signals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

et al. 2010

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“…Of note, lethal arrhythmias are responsible for up to half of the deaths in HF (30). On the contrary, the arrhythmic risk of implantation, homing, engraftment, and differentiation of regenerating cells within the damaged cardiac tissue has constantly been a reason for major concern in the clinical use (15,17,48,73,74). Nevertheless, a number of papers documented a direct prorhythmic (rather than arrhythmic) action of cell therapy (11,27,34,46,50,72,89,90,92,93).…”

Section: Repair Of Infarcted Heart By Local Injection Of C-kit Pos Camentioning

confidence: 99%

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Savi

Bocchi

Rossi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Kit pos cardiac progenitor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF ϩ IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. Adult male Wistar rats (139 rats) with 4-wk-old MI or sham conditions were randomized to receive intramyocardial injection of GFs, CPCs, CPCs ϩ GFs, or vehicle (V). Enhanced green fluorescent protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. Compared with V and at variance with individual CPCs, CPCs ϩ GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy toward sham values. GFs alone reduced arrhythmias by less than CPCs ϩ GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs ϩ GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive antiarrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Connexin-43, Connexin-40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart. cardiac progenitor cells; growth factors and cytokines; myocardial infarction; arrhythmia; cardiac gap junction connexins NEW & NOTEWORTHY Repair of infarcted heart by local injection of c-kit pos cardiac progenitors supplemented with hepatocyte growth factor and IGF-1 has distinctive antiarrhythmic effects involving recovery of Connexin-43, Connexin-40, and Ca v1.2 expression levels differently than progenitors or cytokines alone. This new insight into the impact of regenerative therapies on cardiac electrogenesis has clinical relevance.HEART FAILURE (HF) very often proceeds as a consequence of myocardial infarction (MI) (59) and continues to be a major health problem (49). Over the past 15 yr, cell therapy has emerged as a new strategy aimed at revitalizing dead myocardium, thus circumventing the unfavorable outcome of degenerative heart diseases, including the vicious circle of MI/HF (67). However, results obtained so far in clinical trials with a large sample size using cells of different origin, mainly skeletal myoblasts (44) and bone marrow cells (78), have been contradictor...

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“…For appropriate engraftment, ideal cells should be easy to expand and collect, form stable grafts, be able to properly couple electromechanically with the host cardiomyocytes, and be devoid of arrhythmogenic effects [10,11]. Indeed, a number of experiments in which human stem cell-derived cardiomyocytes transplanted into rodent heart have failed to show adequate electrical coupling of graft to host myocardium, a potentially arrhythmogenic outcome [12].…”

Section: Arrhythmia As a Side Effect Of Cell Transplantationmentioning

confidence: 99%

Stem cells in rhythmology — Short communication

Földes

2011

IMAS

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Abstract:Use of stem cells may transform the medical therapy for acute and chronic heart disease, with a predictable impact rivalling the results of revascularization and device therapies. Many cell types have been studied recently, and promising preclinical and clinical data are available on their efficacy and safety in the setting of various disorders such as arrhythmia and conduction disease. However, there are still many hurdles to be tackled for the routine clinical application of these cells. A better understanding of the biology of stem cells will help in the design of future strategies.

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Electrophysiological Challenges of Cell-Based Myocardial Repair

Cited by 98 publications

References 121 publications

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Stem cells in rhythmology — Short communication

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