Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell–Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine

Gao, Ling; Gregorich, Zachery R.; Zhu, Wuqiang; Mattapally, Saidulu; Oduk, Yasin; Lou, Xi; Kannappan, Ramaswamy; Borovjagin, Anton V.; Walcott, Gregory P.; Pollard, Andrew E.; Fast, Vladimir G.; Hu, Xinyang; Lloyd, Steven G.; Ge, Ying; Zhang, Jianyi

doi:10.1161/circulationaha.117.030785

Cited by 341 publications

(322 citation statements)

References 39 publications

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“…Exosome identification nanoparticle tracking analysis was performed with a NanoSight LM10 (Malvern Instruments, Worcestershire, UK), and protein content in each sample was measured via a MicroBCA protein assay (ThermoFisher Scientific). Incorporation of VEGF was determined by Western blot analysis, as previously described (4). Exosome ultrastructure was analyzed by transmission electron microscopy and negative staining for background identification.…”

Section: H331 Spheroid Transplantation Improve Myocardial Injury In Micementioning

confidence: 99%

Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Mattapally

Zhu

Fast

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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The microenvironment of native heart tissue may be better replicated when cardiomyocytes are cultured in three-dimensional clusters (i.e., spheroids) than in monolayers or as individual cells. Thus, we differentiated human cardiac lineage-induced pluripotent stem cells in cardiomyocytes (hiPSC-CMs) and allowed them to form spheroids and spheroid fusions that were characterized in vitro and evaluated in mice after experimentally induced myocardial infarction (MI). Synchronized contractions were observed within 24 h of spheroid formation, and optical mapping experiments confirmed the presence of both Ca transients and propagating action potentials. In spheroid fusions, the intraspheroid conduction velocity was 7.0 ± 3.8 cm/s on days 1- 2 after formation, whereas the conduction velocity between spheroids increased significantly ( P = 0.003) from 0.8 ± 1.1 cm/s on days 1- 2 to 3.3 ± 1.4 cm/s on day 7. For the murine MI model, five-spheroid fusions (200,000 hiPSC-CMs/spheroid) were embedded in a fibrin patch and the patch was transplanted over the site of infarction. Later (4 wk), echocardiographic measurements of left ventricular ejection fraction and fractional shortening were significantly greater in patch-treated animals than in animals that recovered without the patch, and the engraftment rate was 25.6% or 30% when evaluated histologically or via bioluminescence imaging, respectively. The exosomes released from the spheroid patch seemed to increase cardiac function. In conclusion, our results established the feasibility of using hiPSC-CM spheroids and spheroid fusions for cardiac tissue engineering, and, when fibrin patches containing hiPSC-CM spheroid fusions were evaluated in a murine MI model, the engraftment rate was much higher than the rates we have achieved via the direct intramyocardial injection.

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Section: H331 Spheroid Transplantation Improve Myocardial Injury In Micementioning

confidence: 99%

Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Mattapally

Zhu

Fast

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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“…Transplanted mesenchymal stem cells (MSCs) could then reduce autophagic flux through excreted exosomes containing miR‐125b‐5p in infarcted hearts . Another investigation showed that exosomes released from human cardiac muscle patches appeared to have cytoprotective properties that improved cardiomyocyte survival . This accumulated evidence illustrates that exosomes containing miRNAs beneficially affect infarcted myocardium by bringing about repair and regeneration.…”

Section: Discussionmentioning

confidence: 99%

Exosomal miRNAs as potential biomarkers for acute myocardial infarction

et al. 2019

IUBMB Life

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microRNAs (miRNAs) can be used as biomarkers for acute myocardial infarction (AMI). However, few reports have focused on the value of exosomal miRNAs in the mechanism of the pathophysiological process from stable coronary artery disease (SCAD) to AMI. Exosomes were isolated via ultracentrifugation after serum samples were collected. The exosomes were then identified by transmission electron microscopy, western blotting, and nanoparticle tracking analysis. The differential expression of miRNAs in exosomes from six AMI and six matching SCAD patients was screened using the Agilent Human miRNA Microarray Kit. Target genes of the candidate miRNAs were predicted via an online miRNA database, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. Further validation was conducted through quantitative real‐time polymerase chain reaction with 60 exosome samples. The expression of 13 miRNAs was significantly downregulated in the AMI samples compared with the SCAD samples. In addition, we identified various target genes that are mainly involved in the pathways of cardiac rehabilitation and remodelling. Validation of the expression of candidate miRNAs indicated that exosomal miR‐1915‐3p, miR‐4,507, and miR‐3,656 were significantly less expressed in AMI samples than in SCAD samples, and area under the receiver‐operating‐characteristic curve (AUC) analysis showed that the expression of these miRNAs resulted in good predictive accuracy [miR‐1915‐3p (AUC: 0.772); miR‐4,507 (AUC: 0.684); and miR‐3,656 (AUC: 0.771)], suggesting that these serum exosomal miRNAs might be predictive for AMI at an early stage. Hence, exosomal miRNAs might play an important role in the pathophysiology of AMI and could serve as diagnostic biomarkers.

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“…The conduction velocities of these cardiac patches increased significantly as the purity of the cardiomyocytes increased [33]. Human cardiac muscle patches transplanted into swine were shown to prominently improve left ventricular function and myocardial stress, promote myocardial hypertrophy, and reduce myocardial apoptosis [34]. It was shown that a 3D culture suppressed smooth muscle -actin content and increased the expression of several cardiac markers [35].…”

Section: Biophysical and Biochemical Factorsmentioning

confidence: 99%

Engineered Maturation Approaches of Human Pluripotent Stem Cell-Derived Ventricular Cardiomyocytes

Wang

2019

Cells

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Heart diseases such as myocardial infarction and myocardial ischemia are paroxysmal and fatal in clinical practice. Cardiomyocytes (CMs) differentiated from human pluripotent stem cells provide a promising approach to myocardium regeneration therapy. Identifying the maturity level of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is currently the main challenge for pathophysiology and therapeutics. In this review, we describe current maturity indicators for cardiac microtissue and microdevice cultivation technologies that accelerate cardiac maturation. It may provide insights into regenerative medicine, drug cardiotoxicity testing, and preclinical safety testing.

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Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell–Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine

Cited by 341 publications

References 39 publications

Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Exosomal miRNAs as potential biomarkers for acute myocardial infarction

Engineered Maturation Approaches of Human Pluripotent Stem Cell-Derived Ventricular Cardiomyocytes

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