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Ipsc derived cardiomyopathy

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https://www.readbyqxmd.com/read/28439558/crispr-cpf1-correction-of-muscular-dystrophy-mutations-in-human-cardiomyocytes-and-mice
#1
Yu Zhang, Chengzu Long, Hui Li, John R McAnally, Kedryn K Baskin, John M Shelton, Rhonda Bassel-Duby, Eric N Olson
Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. We deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28395747/generation-of-induced-pluripotent-stem-cells-ipscs-from-a-hypertrophic-cardiomyopathy-patient-with-the-pathogenic-variant-p-val698ala-in-beta-myosin-heavy-chain-myh7-gene
#2
Samantha Barratt Ross, Stuart T Fraser, Natalie Nowak, Christopher Semsarian
Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the whole blood of a 43-year-old male with hypertrophic cardiomyopathy (HCM) who carries the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7). Patient-derived PBMCs were reprogrammed using non-integrative episomal vectors containing reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry the pathogenic MYH7 variant p...
April 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28395744/peripheral-blood-derived-induced-pluripotent-stem-cells-ipscs-from-a-female-with-familial-hypertrophic-cardiomyopathy
#3
Samantha Barratt Ross, Stuart T Fraser, Richard D Bagnall, Christopher Semsarian
Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) obtained from a 62-year-old female with familial hypertrophic cardiomyopathy (HCM). PBMCs were reprogrammed to a pluripotent state following transfection with non-integrative episomal vectors carrying reprogramming factors OCT4, SOX2, LIN28, KLF4 and L-MYC. iPSCs were shown to express pluripotency markers, possess trilineage differentiation potential, carry rare variants identified in DNA isolated directly from the patient's whole blood, have a normal karyotype and no longer carry episomal vectors for reprogramming...
April 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28391974/generation-of-induced-pluripotent-stem-cells-as-disease-modelling-of-nlsdm
#4
D Tavian, S Missaglia, M Castagnetta, D Degiorgio, E M Pennisi, R A Coleman, P Dell'Era, C Mora, C Angelini, D A Coviello
Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids...
April 3, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28336914/inhibition-of-serum-and-glucocorticoid-regulated-kinase-1-as-novel-therapy-for-cardiac-arrhythmia-disorders
#5
Vassilios J Bezzerides, Aifeng Zhang, Ling Xiao, Bridget Simonson, Santosh A Khedkar, Shiro Baba, Filomena Ottaviano, Stacey Lynch, Katherine Hessler, Alan C Rigby, David Milan, Saumya Das, Anthony Rosenzweig
Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28246128/a-comprehensive-talen-based-knockout-library-for-generating-human-induced-pluripotent-stem-cell-based-models-for-cardiovascular-diseases
#6
Ioannis Karakikes, Vittavat Termglinchan, Diana A Cepeda, Jaecheol Lee, Sebastian Diecke, Ayal Hendel, Ilanit Itzhaki, Mohamed Ameen, Rajani Shrestha, Haodi Wu, Ning Ma, Ning-Yi Shao, Timon Seeger, Nicole A Woo, Kitchener D Wilson, Elena Matsa, Matthew H Porteus, Vittorio Sebastiano, Joseph C Wu
Rationale: Targeted genetic engineering using programmable nucleases such as transcription activator-like effector nucleases (TALENs) is a valuable tool for precise, site-specific genetic modification in the human genome. Objective: The emergence of novel technologies such as human induced pluripotent stem cells (iPSCs) and nuclease-mediated genome editing represent a unique opportunity for studying cardiovascular diseases in vitro. Methods and Results: By incorporating extensive literature and database searches, we designed a collection of TALEN constructs to knockout (KO) eighty-eight human genes that are associated with cardiomyopathies and congenital heart diseases...
February 28, 2017: Circulation Research
https://www.readbyqxmd.com/read/28218286/vinculin-variant-m94i-identified-in-sudden-unexplained-nocturnal-death-syndrome-decreases-cardiac-sodium-current
#7
Jianding Cheng, John W Kyle, Brandi Wiedmeyer, Di Lang, Ravi Vaidyanathan, Jonathan C Makielski
Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS. A rare heterozygous variant VCL-M94I was found in a SUNDS victim who suffered sudden nocturnal tachypnea and lacked pathogenic variants in known arrhythmia-causing genes. VCL was identified to interact with SCN5A in vitro/vivo. The VCL-M94I was co-expressed with the cardiac sodium channel in HEK293 cells and also overexpressed in induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM)...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28170191/metabolomic-profiling-of-pompe-disease-induced-pluripotent-stem-cell-derived-cardiomyocytes-reveals-that-oxidative-stress-is-associated-with-cardiac-and-skeletal-muscle-pathology
#8
Yohei Sato, Hiroshi Kobayashi, Takashi Higuchi, Yohta Shimada, Hiroyuki Ida, Toya Ohashi
Pompe disease (PD) is a lysosomal storage disease that is caused by a deficiency of the acid α-glucosidase, which results in glycogen accumulation in the lysosome. The major clinical symptoms of PD include skeletal muscle weakness, respiratory failure, and cardiac hypertrophy. Based on its severity and symptom onset, PD is classified into infantile and late-onset forms. Lysosomal accumulation of glycogen can promote many types of cellular dysfunction, such as autophagic dysfunction, endoplasmic reticulum stress, and abnormal calcium signaling within skeletal muscle...
January 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28130338/exosomes-from-pediatric-dilated-cardiomyopathy-patients-modulate-a-pathological-response-in-cardiomyocytes
#9
Xuan Jiang, Juliana Sucharov, Brian L Stauffer, Shelley D Miyamoto, Carmen C Sucharov
Stimulation of the renin-angiotensin-aldosterone system (RAAS) and β-adrenergic receptors plays an important role in adult heart failure (HF). Despite the demonstrated benefits of RAAS inhibition and β-adrenergic receptor blockade in adult HF patients, no substantial improvement in survival rate has been observed in children with HF. This suggests that the underlying disease mechanism is uniquely regulated in pediatric HF. Here, we show that treatment of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) with serum from pediatric dilated cardiomyopathy (DCM) patients induces pathologic changes in gene expression, which occurs independently of the RAAS and adrenergic systems, suggesting that serum circulating factors play an important role in cardiac remodeling...
January 27, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28104773/exosomes-generated-from-ipsc-derivatives-new-direction-for-stem-cell-therapy-in-human-heart-diseases
#10
REVIEW
Ji-Hye Jung, Xuebin Fu, Phillip C Yang
Cardiovascular disease (CVD) is the leading cause of death in modern society. The adult heart innately lacks the capacity to repair and regenerate the damaged myocardium from ischemic injury. Limited understanding of cardiac tissue repair process hampers the development of effective therapeutic solutions to treat CVD such as ischemic cardiomyopathy. In recent years, rapid emergence of induced pluripotent stem cells (iPSC) and iPSC-derived cardiomyocytes presents a valuable opportunity to replenish the functional cells to the heart...
January 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/27888626/interleukin-18-deteriorates-fabry-cardiomyopathy-and-contributes-to-the-development-of-left-ventricular-hypertrophy-in-fabry-patients-with-gla-ivs4-919-g-a-mutation
#11
Yueh Chien, Chian-Shiu Chien, Huai-Chih Chiang, Wei-Lin Huang, Shih-Jie Chou, Wei-Chao Chang, Yuh-Lih Chang, Hsin-Bang Leu, Kuan-Hsuan Chen, Kang-Ling Wang, Ying-Hsiu Lai, Yung-Yang Liu, Kai-Hsi Lu, Hsin-Yang Li, Yen-Jen Sung, Yuh-Jyh Jong, Yann-Jang Chen, Chung-Hsuan Chen, Wen-Chung Yu
RATIONALE: A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown. OBJECTIVE: Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27678261/amelioration-of-x-linked-related-autophagy-failure-in-danon-disease-with-dna-methylation-inhibitor
#12
Kwong-Man Ng, Pamela Y Mok, Amy W Butler, Jenny C Y Ho, Shing-Wan Choi, Yee-Ki Lee, Wing-Hon Lai, Ka-Wing Au, Yee-Man Lau, Lai-Yung Wong, Miguel A Esteban, Chung-Wah Siu, Pak C Sham, Alan Colman, Hung-Fat Tse
BACKGROUND: Danon disease is an X-linked disorder that leads to fatal cardiomyopathy caused by a deficiency in lysosome-associated membrane protein-2 (LAMP2). In female patients, a later onset and less severe clinical phenotype have been attributed to the random inactivation of the X chromosome carrying the mutant diseased allele. We generated a patient-specific induced pluripotent stem cell (iPSCs)-based model of Danon disease to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor...
November 1, 2016: Circulation
https://www.readbyqxmd.com/read/27642787/ipsc-derived-cardiomyocytes-reveal-abnormal-tgf-%C3%AE-signalling-in-left-ventricular-non-compaction-cardiomyopathy
#13
Kazuki Kodo, Sang-Ging Ong, Fereshteh Jahanbani, Vittavat Termglinchan, Keiichi Hirono, Kolsoum InanlooRahatloo, Antje D Ebert, Praveen Shukla, Oscar J Abilez, Jared M Churko, Ioannis Karakikes, Gwanghyun Jung, Fukiko Ichida, Sean M Wu, Michael P Snyder, Daniel Bernstein, Joseph C Wu
Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and its pathogenesis has been associated with the developmental defect of the embryonic myocardium. We show that patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from LVNC patients carrying a mutation in the cardiac transcription factor TBX20 recapitulate a key aspect of the pathological phenotype at the single-cell level and this was associated with perturbed transforming growth factor beta (TGF-β) signalling...
October 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27641650/ipsc-mscs-with-high-intrinsic-miro1-and-sensitivity-to-tnf-%C3%AE-yield-efficacious-mitochondrial-transfer-to-rescue-anthracycline-induced-cardiomyopathy
#14
Yuelin Zhang, Zhendong Yu, Dan Jiang, Xiaoting Liang, Songyan Liao, Zhao Zhang, Wensheng Yue, Xiang Li, Sin-Ming Chiu, Yuet-Hung Chai, Yingmin Liang, Yenyen Chow, Shuo Han, Aimin Xu, Hung-Fat Tse, Qizhou Lian
Mesenchymal stem cells (MSCs) can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM) damage, although the underlying mechanisms remain elusive. We determined that the superior efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs) compared with bone marrow-derived MSCs (BM-MSCs) is due to high expression of intrinsic Rho GTPase 1 (MIRO1). Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway...
October 11, 2016: Stem Cell Reports
https://www.readbyqxmd.com/read/27538429/metabolomic-profiling-of-pompe-disease-induced-pluripotent-stem-cell-derived-cardiomyocytes-reveals-that-oxidative-stress-is-associated-with-cardiac-and-skeletal-muscle-pathology
#15
Yohei Sato, Hiroshi Kobayashi, Takashi Higuchi, Yohta Shimada, Hiroyuki Ida, Toya Ohashi
: Pompe disease (PD) is a lysosomal storage disease that is caused by a deficiency of the acid α-glucosidase, which results in glycogen accumulation in the lysosome. The major clinical symptoms of PD include skeletal muscle weakness, respiratory failure, and cardiac hypertrophy. Based on its severity and symptom onset, PD is classified into infantile and late-onset forms. Lysosomal accumulation of glycogen can promote many types of cellular dysfunction, such as autophagic dysfunction, endoplasmic reticulum stress, and abnormal calcium signaling within skeletal muscle...
August 18, 2016: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/27332740/high-throughput-bioassay-for-beta1-adrenoceptor-autoantibody-detection
#16
Shivanjali Joshi-Barr, Annekathrin Haberland, Sabine Bartel, Johannes Müller, Ted Choi, Gerd Wallukat
BACKGROUND: While the involvement of adrenergic beta1-autoantibodies (beta1-AABs) in pathogenesis of cardiomyopathies is well established as are the benefits associated with autoantibody removal by immunoapheresis, the development of drugs neutralizing beta1-AABs in-vivo has been slowed due to a lack of high throughput autoantibody analytics. Highly scalable routine diagnostics involving immobilized binding partners have mostly failed in comparison to the laborious bioassays, which are difficult to scale up, but present the most reliable and sensitive tools for detecting the beta1-autoantibodies...
September 15, 2016: International Journal of Cardiology
https://www.readbyqxmd.com/read/27296521/induced-pluripotent-stem-cells-in-the-inherited-cardiomyopathies-from-disease-mechanisms-to-novel-therapies
#17
REVIEW
Samantha Barratt Ross, Stuart T Fraser, Christopher Semsarian
Inherited cardiomyopathies lead to diverse clinical outcomes including heart failure, arrhythmias, and sudden death. Mutations in over 100 genes have been implicated in the pathogenesis of genetic heart diseases, including the main inherited cardiomyopathies, such as hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies. Understanding how these gene mutations lead to clinical disease and the various secondary genetic and environmental factors, which may modify the clinical phenotype, are key areas of research ultimately influencing diagnosis and management of patients...
November 2016: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/27226619/the-human-343delt-hspb5-chaperone-associated-with-early-onset-skeletal-myopathy-causes-defects-in-protein-solubility
#18
Katie A Mitzelfelt, Pattraranee Limphong, Melinda J Choi, Frances D L Kondrat, Shuping Lai, Kurt D Kolander, Wai-Meng Kwok, Qiang Dai, Michael N Grzybowski, Huali Zhang, Graydon M Taylor, Qiang Lui, Mai T Thao, Judith A Hudson, Rita Barresi, Kate Bushby, Heinz Jungbluth, Elizabeth Wraige, Aron M Geurts, Justin L P Benesch, Michael Riedel, Elisabeth S Christians, Alex C Minella, Ivor J Benjamin
Mutations of HSPB5 (also known as CRYAB or αB-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aimed to investigate the pathological mechanisms involved in an early-onset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/343delT) and BHK21 cells, a cell line lacking endogenous HSPB5 expression...
July 15, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27199119/a-myosin-activator-improves-actin-assembly-and-sarcomere-function-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-with-a-troponin-t-point-mutation
#19
K M Broughton, J Li, E Sarmah, C M Warren, Y-H Lin, M P Henze, V Sanchez-Freire, R J Solaro, B Russell
We have investigated cardiac myocytes derived from human-induced pluripotent stem cells (iPSC-CMs) from two normal control and two family members expressing a mutant cardiac troponin T (cTnT-R173W) linked to dilated cardiomyopathy (DCM). cTnT is a regulatory protein of the sarcomeric thin filament. The loss of this basic charge, which is strategically located to control tension, has consequences leading to progressive DCM. iPSC-CMs serve as a valuable platform for understanding clinically relevant mutations in sarcomeric proteins; however, there are important questions to be addressed with regard to myocyte adaptation that we model here by plating iPSC-CMs on softer substrates (100 kPa) to create a more physiologic environment during recovery and maturation of iPSC-CMs after thawing from cryopreservation...
July 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/27105042/pharmacological-modulation-of-calcium-homeostasis-in-familial-dilated-cardiomyopathy-an-in-vitro-analysis-from-an-rbm20-patient-derived-ipsc-model
#20
S P Wyles, S C Hrstka, S Reyes, A Terzic, T M Olson, T J Nelson
For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca(2+) ), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here, we characterized the effect of β-adrenergic stress in familial dilated cardiomyopathy (DCM) using human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that β-adrenergic stimulation accelerated defective Ca(2+) homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC-CMs...
June 2016: Clinical and Translational Science
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