Preclinical Safety Evaluation of Allogeneic Induced Pluripotent Stem Cell-Based Therapy in a Swine Model of Myocardial Infarction

2017 ◽  
Vol 23 (11) ◽  
pp. 736-744 ◽  
Author(s):  
Carolina Gálvez-Montón ◽  
Carolina Soler-Botija ◽  
Oriol Iborra-Egea ◽  
Idoia Díaz-Güemes ◽  
Mercè Martí ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Safety Evaluation ◽  
Induced Pluripotent Stem Cell ◽  
Swine Model ◽  
Cell Based Therapy ◽  
Induced Pluripotent ◽  
Preclinical Safety

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 Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes

2020 ◽  
Vol 176 (1) ◽  
pp. 103-123 ◽  
Author(s):  
Umber Saleem ◽  
Berend J van Meer ◽  
Puspita A Katili ◽  
Nurul A N Mohd Yusof ◽  
Ingra Mannhardt ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Signal To Noise Ratio ◽  
Safety Evaluation ◽  
Primary Source ◽  
Induced Pluripotent Stem Cell ◽  
Drug Induced ◽  
Inotropic Effects ◽  
Induced Pluripotent ◽  
Improving Accuracy

Abstract Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHTs). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-noise ratio, reduce spontaneous beat rate to ≤ 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHTs. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHTs. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHTs, these parameters typically served as the primary source of predictivity in 2D. The reliance of these “secondary” parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation.

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