Nitric oxide mediated cytoprotection against simulated ischemia/reperfusion caused injury in induced pluripotent stem cell-derived cardiac myocytes

2015 ◽  
Vol 75 ◽  
pp. 58
Author(s):  
A. Görbe ◽  
J. Pálóczi ◽  
E. Ruivo ◽  
Á. Szántai ◽  
R. Gáspár ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cell ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cell ◽  
Ischemia Reperfusion ◽  
Induced Pluripotent Stem Cell ◽  
Simulated Ischemia ◽  
Induced Pluripotent

Biophysical comparison of sodium currents in native cardiac myocytes and human induced pluripotent stem cell-derived cardiomyocytes

2018 ◽  
Vol 90 ◽  
pp. 19-30 ◽  
Author(s):  
Robert J. Goodrow ◽  
Suveer Desai ◽  
Jacqueline A. Treat ◽  
Brian K. Panama ◽  
Mayurika Desai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Sodium Currents ◽  
Induced Pluripotent

scholarly journals N-cadherin overexpression enhances the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes in infarcted mouse hearts

2019 ◽  
Vol 116 (3) ◽  
pp. 671-685 ◽  
Author(s):  
Xi Lou ◽  
Meng Zhao ◽  
Chengming Fan ◽  
Vladimir G Fast ◽  
Mani T Valarmathi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Infarct Size ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cell ◽  
Myogenic Differentiation ◽  
Functional Integration ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Cardiac Functions ◽  
Induced Pluripotent

Abstract Aims In regenerative medicine, cellular cardiomyoplasty is one of the promising options for treating myocardial infarction (MI); however, the efficacy of such treatment has shown to be limited due to poor survival and/or functional integration of implanted cells. Within the heart, the adhesion between cardiac myocytes (CMs) is mediated by N-cadherin (CDH2) and is critical for the heart to function as an electromechanical syncytium. In this study, we have investigated whether the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) can be enhanced through CDH2 overexpression. Methods and results CDH2-hiPSC-CMs and control wild-type (WT)-hiPSC-CMs were cultured in myogenic differentiation medium for 28 days. Using a mouse MI model, the cell survival/engraftment rate, infarct size, and cardiac functions were evaluated post-MI, at Day 7 or Day 28. In vitro, conduction velocities were significantly greater in CDH2-hiPSC-CMs than in WT-hiPSC-CMs. While, in vivo, measurements of cardiac functions: left ventricular (LV) ejection fraction, reduction in infarct size, and the cell engraftment rate were significantly higher in CDH2-hiPSC-CMs treated MI group than in WT-hiPSC-CMs treated MI group. Mechanistically, paracrine activation of ERK signal transduction pathway by CDH2-hiPSC-CMs, significantly induced neo-vasculogenesis, resulting in a higher survival of implanted cells. Conclusion Collectively, these data suggest that CDH2 overexpression enhances not only the survival/engraftment of cultured CDH2-hiPSC-CMs, but also the functional integration of these cells, consequently, the augmentation of the reparative properties of implanted CDH2-hiPSC-CMs in the failing hearts.

Abstract 14878: Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes vs Mesenchymal Stem Cells Demonstrate Differential Restoration of Myocardial Function in a Porcine Ischemia Reperfusion Injury Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Connor G OBrien ◽  
Evgeniya Vaskova ◽  
Yuko Tada ◽  
Jihye Jung ◽  
Gentaro Ikeda ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Ischemia Reperfusion ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Myocardial Scar ◽  
Injury Model ◽  
Induced Pluripotent

Introduction: Coronary artery disease is a leading cause of death worldwide. Ischemic injury leads to myocardial dysfunction, resulting in heart failure. Exosomes have emerged as a promising therapeutic for restoring the failing heart. Fundamental questions such as cell of origin and molecular cargo for optimal therapeutic effect are areas of intense research. Our lab has shown that the exosomes from bone marrow derived mesenchymal stem cells (MSC-Ex) and induced pluripotent stem cell derived cardiomyocytes (iCM-Ex) both restore injured murine myocardium. These results led us to compare the therapeutic effects of MSC-Ex vs. iCM-Ex in a porcine myocardial ischemia reperfusion (IR) injury model, a step toward predicting efficacy in humans. Hypothesis: iCM-Ex is superior to MSC-Ex in restoring the injured porcine myocardium. Methods and Results: Pigs underwent ischemia reperfusion (IR) injury, consisting of 1 hour percutaneous balloon occlusion of the proximal left anterior descending artery immediately distal to the first septal artery. Following IR injury, 5 x 10 11 exosomes were delivered in ten, 500μL intramyocardial injections using a BioCardio Helix™ catheter. Biplane ventriculography was used to target the peri-infarct region. At 2- and 4-weeks post-infarct, pigs underwent cardiac MRI (cMRI) with ciné, delayed-enhanced (DEMRI) and manganese-enhanced (MEMRI) MRI. Pigs treated with iCM-Ex (n = 5) demonstrated a 41% improvement in left ventricular ejection fraction (LVEF, p = 0.004) and 35% reduction in indexed left ventricular end diastolic volume (p = 0.008) compared to controls while MSC-Ex (N = 5) did not demonstrate significant functional improvement. Furthermore, DEMRI and MEMRI showed a 21% reduction in myocardial scar (p = 0.14) in iCM-Ex treated animals compared to control while MSC-Ex group showed no difference. RNA-seq of the exosomes and transcriptomic analysis of the ex vivo myocardium will delineate the molecular mechanism of action and the putative intracellular pathway. Conclusion: iCM-Ex is superior to MSC-Ex in improving LVEF and reducing myocardial scar formation following ischemic insult. Comparative analysis between iCM-Ex and MSC-Ex is underway to identify the molecular targets that restore the failing heart.

Abstract 16472: Deciphering a Mechanistic Link Between Enhanced Late Sodium Current and Triggered Atrial Fibrillation Using Patient-specific and Gene-corrected Induced Pluripotent Stem Cell-derived Atrial Cardiomyocytes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Liang HONG ◽  
Olivia T Ly ◽  
Hanna Chen ◽  
Arvind Sridhar ◽  
Meihong Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Atrial Fibrillation ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Sodium Current ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Gain Of Function ◽  
Late Sodium Current ◽  
Induced Pluripotent

Introduction: Gain-of-function mutations in SCN5A, which encodes the cardiac sodium channel, have been linked with familial atrial fibrillation (AF). However, the mechanistic link between the late sodium current (I Na,L ) and triggered arrhythmia remains unclear. Hypothesis: To characterize the electrophysiological (EP) phenotype of gain-of-function AF-linked SCN5A mutations, elucidate the underlying cellular mechanisms using patient-specific and gene-corrected (GC) induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs). Methods: We generated iPSC-aCMs from two families carrying SCN5A mutations (E428K and N470K) and control subjects. Whole-cell patch clamp and multi-electrode arrays were recorded to assess the EP phenotypes of the atrial iPSC-CMs. We corrected the E428K iPSC-aCMs using CRISPR/Cas9 gene editing approach (isogenic control). Results: The SCN5A mutation lines displayed abnormal EP properties including increased beating frequency and irregularity with triggered beats characteristic of AF ( Fig. 1 ). E428K iPSC-aCMs displayed spontaneous arrhythmogenic activity with beat-to-beat irregularity ( Fig. 1 A-D ) with the prolonged APD ( Fig. 1 E-H ) associated with enhanced I Na,L ( Fig. 1 I-L ). In contrast, expression of SCN5A -E428K in heterologous expression system failed to show enhanced I Na,L . The gene-corrected E428K iPSC-aCMs normalized the aberrant EP phenotype. Gene expression profiling revealed differential expression of calcium and potassium channel homeostasis and nitric oxide mediated signal transduction which could result in EP remodeling of atrial CMs. Conclusions: Patient-specific and gene-corrected iPSC-aCMs exhibited striking ex-vivo EP phenotype of an AF-causing SCN5A gain-of-function mutation that produced minimal changes in-vitro . We established a mechanistic link between enhanced I Na,L , ion channel remodeling and nitric oxide signaling pathways, and triggered AF.

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