scholarly journals Investigating LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2021 ◽  
Vol 22 (15) ◽  
pp. 7874
Author(s):  
Yuval Shemer ◽  
Lucy N. Mekies ◽  
Ronen Ben Jehuda ◽  
Polina Baskin ◽  
Rita Shulman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Action Potential ◽  
Dilated Cardiomyopathy ◽  
Pluripotent Stem Cell ◽  
Systolic Function ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Lmna Gene ◽  
Beat Rate ◽  
Induced Pluripotent

LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients’ induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (If) density; (2) prolonged action potential duration and increased L-type Ca2+ current (ICa,L) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na+/Ca2+ exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.

Abstract 16282: The Development of the New Treatment for Distressed Microvascular Dysfunction in Porcine Dilated Cardiomyopathy Model Using Induced Pluripotent Stem Cell Derived Cardiomyocyte Sheet

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kota Suzuki ◽  
Shigeru Miyagawa ◽  
Emiko Ito ◽  
Akima Harada ◽  
Takuji Kawamura ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dilated Cardiomyopathy ◽  
Pluripotent Stem Cell ◽  
Sham Group ◽  
Immunosuppressive Agents ◽  
Systolic Pressure ◽  
Induced Pluripotent Stem Cell ◽  
Microvascular Dysfunction ◽  
Left Ventricular ◽  
Induced Pluripotent

Introduction: The progression of dilated cardiomyopathy (DCM) mainly involves genetic mutations or ischemia at the cellular level, leading to microvascular dysfunction associated with cell death, interstitial fibrosis, and high wall stress. Radical treatment of DCM requires how to ameliorate its microcirculation and integrate cardiomyocytes created ex vivo into recipient myocardium. Hypothesis: The induced pluripotent stem cell derived cardiomyocyte sheets (iPS-sheet) has therapeutic potential by the improvement of microcirculation in a porcine DCM model. Methods: The iPS-sheets were generated from clinical grade human iPS cells. A DCM model was created by tachycardia pacing, and iPS-sheet was transplanted with immunosuppressive agents 1 month after the initiation of the pacing. We compared the therapeutic efficacy functionally and pathologically between the iPS-sheet transplant group (iPS-group) and the sham group after 1 month of transplantation. Results: On echocardiography, the iPS group showed a significant improvement in contractility compared to the sham group (LVEF 4 weeks after transplantation iPS vs. sham 49.0±6.5% vs. 36.4±3.3%, p<0.05, Figure A). Pressure-volume loop analysis revealed that a significant decrease in left ventricular end diastolic pressure and an improvement in end-systolic pressure-volume relationship in the iPS group (Figure B). Ammonia PET showed improvement in myocardial blood flow at both rest and stress in iPS group (Figure C). Histological analysis revealed that the density of CD31-positive capillaries in transplanted area was significantly greater in the iPS group than the sham group. Immunostaining revealed iPS-sheet were detected on the epicardium of the distressed myocardium (Figure D). Conclusions: The iPS sheet showed engraftment in distressed myocardium, leading to amelioration in cardiac function through improving microcirculation with angiogenesis in porcine DCM model.

scholarly journals Functional abnormalities in induced Pluripotent Stem Cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy

PLoS ONE ◽  
2018 ◽  
Vol 13 (10) ◽  
pp. e0205719 ◽  
Author(s):  
Revital Schick ◽  
Lucy N. Mekies ◽  
Yuval Shemer ◽  
Binyamin Eisen ◽  
Tova Hallas ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dilated Cardiomyopathy ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

Abstract 205: Feasibility and Testing of a Human Induced Pluripotent Stem Cell Derived Cardiac Patch in a Pre-clinical Swine Model of CHF

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jordan J Lancaster ◽  
Ike Chinyere ◽  
Bin Na Kim ◽  
Sherry Daugherty ◽  
Samuel Kim ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Dermal Fibroblasts ◽  
Swine Model ◽  
Induced Pluripotent ◽  
Cardiac Patch

Introduction: Previously we have demonstrated that a tissue engineered heart patch comprised of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and fibroblasts improves both left ventricular (LV) systolic and diastolic function in a rat model of CHF. In this study we tested the feasibility of upscaling cardiac patch size and surgical deployment in a swine model of CHF to test clinical utility. Methods: Four male Gottingen mini swine 20-25kg and three domestic swine 50-60kg were infarcted using percutaneous methods. Embolizing coils were deployed via catheter distal to the first diagonal branch of the left anterior descending (LAD) coronary artery and animals recovered for 4 weeks. Cardiac patches engineered with bio absorbable polygalactin-910 knitted mesh, dermal fibroblasts and hiPSC-CMs were cultured and implanted on the infarcted epicardium 4 weeks after MI. Cardiac magnetic resonance imaging was performed at baseline, 4 and 8 weeks post MI. All swine were implanted with continuous event recorders to acquire surface electrocardiogram during the entire study. In addition quality of life and functional capacity were assessed through video monitoring and treadmill exertion testing respectively. Infarct size was determined through 2,3,5-triphenyltetrazolium chloride staining. Results: LAD occlusion resulted in a significant (P<0.05) decrease EF (15%), and increase in EDV (59%) and ESV (100%). Average TIMI score decreased from 3.0±0 at time of MI to 1.5±0.6 4wks post MI. Cardiac patches were upsized to 6cm diameter for application in the swine. Patches displayed synchronous and spontaneous contractions within 48hrs. The 6cm patches, when implanted effectively covered the infarcted region bridging viable myocardium. Surgical handling and epicardial deployment was successfully accomplished via median sternotomy. The patches were robust in nature and could be deployed via a minimally invasive robotic procedure. No adverse arrhythmic activity was observed. Implantation of the cardiac patch restored activity levels (quality of life) of patch treated swine vs CHF controls. Conclusion: Our hiPSC-CM cardiac patch can be constructed in a clinical size, easily handled and implanted on the epicardium of the infarcted heart.

Abstract 16007: Functional Comparison of Human Embryonic Stem Cell- versus Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Rat Ischemic Myocardial Infarction Model

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Wenyi Chen ◽  
Johannes Riegler ◽  
Elena Matsa ◽  
Qi Shen ◽  
Haodi Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Cardiac Function ◽  
Embryonic Stem Cell ◽  
Pluripotent Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Induced Pluripotent

Introduction: Both human embryonic stem cell-derived cardiomyocytes (ESC-CMs) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can serve as an unlimited cell source for cardiac regenerative therapy. However, the functional equivalency of both approaches has not been previously reported. Here we performed head-to-head comparison on the beneficial effects of ESC-CM and iPSC-CMs in restoring cardiac function in a rat myocardial infarction (MI) model. Methods & Results: Human ESCs and iPSCs were differentiated into cardiomyocytes using small molecules. FACS analysis confirmed ~85% and ~83% of cells differentiated from ESCs and iPSCs, respectively, were positive for cardiac troponin T, and immunofluorescence staining demonstrated that ESC-CMs and iPSC-CMs have striated sarcomeric structure (Figure A-B). Both ESC-CMs and iPSC-CMs displayed similar maturity for calcium handling (transient amplitude: ΔF/F 0 = 3.8±0.3; time to peak: ~200 ms; 50% transient duration: ~400 ms). qRT-PCR showed that ESC-CMs and iPSC-CMs expressed CASQ2, GJA5, KCNJ2, KCNJ5, MYH6, MYH7, and SCN5A at comparable levels to human fetal heart tissue. Next, ESC-CMs and iPSC-CMs were injected into the left ventricular free wall of infarcted hearts (adult nude rats; n=14, 10, respectively). Cardiac function was assessed by MRI one month post cell injection and the hearts were harvested and stained for human cardiac markers. Both ESC-CMs and iPSC-CMs could engraft in ischemic rat hearts (Figure C). Comprehensive functional analysis with small animal magnetic resonance imaging (MRI), echocardiography, and pressure-volume loop analysis are underway. Conclusion: We set out to perform head to head comparison for the first time that iPSC-CMs may facilitate cardiac repair at comparable levels to ESC-CMs. Unlike allogeneic ESC-CM therapy, autologous iPSC-CMs could be used to overcome immune rejection for cardiac cell transplantation in the future.

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.

Sign in / Sign up

Export Citation Format

Share Document