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Ipsc derived cardiomyopathy

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...
November 24, 2016: Oncotarget
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...
September 27, 2016: Circulation
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
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
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
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
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...
May 11, 2016: Trends in Cardiovascular Medicine
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
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
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
Muhammad Z Afzal, Melanie Reiter, Courtney Gastonguay, Jered V McGivern, Xuan Guan, Zhi-Dong Ge, David L Mack, Martin K Childers, Allison D Ebert, Jennifer L Strande
BACKGROUND: Dystrophin-deficient cardiomyopathy is a growing clinical problem without targeted treatments. We investigated whether nicorandil promotes cardioprotection in human dystrophin-deficient induced pluripotent stem cell (iPSC)-derived cardiomyocytes and the muscular dystrophy mdx mouse heart. METHODS AND RESULTS: Dystrophin-deficient iPSC-derived cardiomyocytes had decreased levels of endothelial nitric oxide synthase and neuronal nitric oxide synthase. The dystrophin-deficient cardiomyocytes had increased cell injury and death after 2 hours of stress and recovery...
November 2016: Journal of Cardiovascular Pharmacology and Therapeutics
Ana Saric, Karine Andreau, Anne-Sophie Armand, Ian M Møller, Patrice X Petit
Mutations in the gene encoding the enzyme tafazzin, TAZ, cause Barth syndrome (BTHS). Individuals with this X-linked multisystem disorder present cardiomyopathy (CM) (often dilated), skeletal muscle weakness, neutropenia, growth retardation, and 3-methylglutaconic aciduria. Biopsies of the heart, liver and skeletal muscle of patients have revealed mitochondrial malformations and dysfunctions. It is the purpose of this review to summarize recent results of studies on various animal or cell models of Barth syndrome, which have characterized biochemically the strong cellular defects associated with TAZ mutations...
2015: Frontiers in Genetics
Xiao-Hua Zhang, Martin Morad
Derivation of cardiomyocyte cell lines from human fibroblasts (induced pluripotent stem cells, iPSCs) has made it possible not only to investigate the electrophysiological and Ca(2+) signaling properties of these cells, but also to determine the altered electrophysiological and Ca(2+)-signaling profiles of such cells lines derived from patients expressing mutation-inducing pathologies. This approach has the potential of generating in vitro human models of cardiovascular diseases where cellular pathology can be investigated in detail and possibly specific pharmacotherapy developed...
March 2016: Cell Calcium
Young Wook Chun, David E Voyles, Rutwik Rath, Lucas H Hofmeister, Timothy C Boire, Henry Wilcox, Jae Han Lee, Leon M Bellan, Charles C Hong, Hak-Joon Sung
Primary dilated cardiomyopathy (DCM) is a non-ischemic heart disease with impaired pumping function of the heart. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a healthy volunteer and a primary DCM patient to investigate the impact of DCM on iPSC-CMs׳ responses to different types of anisotropic strain. A bioreactor system was established that generates cardiac-mimetic forces of 150 kPa at 5% anisotropic cyclic strain and 1 Hz frequency. After confirming cardiac induction of the iPSCs, it was determined that fibronectin was favorable to other extracellular matrix protein coatings (gelatin, laminin, vitronectin) in terms of viable cell area and density, and was therefore selected as the coating for further study...
November 5, 2015: Journal of Biomechanics
Jesse Macadangdang, Xuan Guan, Alec S T Smith, Rachel Lucero, Stefan Czerniecki, Martin K Childers, David L Mack, Deok-Ho Kim
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) offer unprecedented opportunities to study inherited heart conditions in vitro, but are phenotypically immature, limiting their ability to effectively model adult-onset diseases. Cardiomyopathy is becoming the leading cause of death in patients with Duchenne muscular dystrophy (DMD), but the pathogenesis of this disease phenotype is not fully understood. Therefore, we aimed to test whether biomimetic nanotopography could further stratify the disease phenotype of DMD hiPSC-CMs to create more translationally relevant cardiomyocytes for disease modeling applications...
September 2015: Cellular and Molecular Bioengineering
Atsushi Tanaka, Shinsuke Yuasa, Koichi Node, Keiichi Fukuda
The generation of induced pluripotent stem cells (iPSCs) has opened up a new scientific frontier in medicine. This technology has made it possible to obtain pluripotent stem cells from individuals with genetic disorders. Because iPSCs carry the identical genetic anomalies related to those disorders, iPSCs are an ideal platform for medical research. The pathophysiological cellular phenotypes of genetically heritable heart diseases such as arrhythmias and cardiomyopathies, have been modeled on cell culture dishes using disease-specific iPSC-derived cardiomyocytes...
2015: International Journal of Molecular Sciences
Yohei Sato, Hiroshi Kobayashi, Takashi Higuchi, Yohta Shimada, Takumi Era, Shigemi Kimura, Yoshikatsu Eto, Hiroyuki Ida, Toya Ohashi
Pompe disease is an autosomal recessive inherited metabolic disease caused by deficiency of acid α-glucosidase (GAA). Glycogen accumulation is seen in the affected organ such as skeletal muscle, heart, and liver. Hypertrophic cardiomyopathy is frequently seen in the infantile onset Pompe disease. On the other hand, cardiovascular complication of the late-onset Pompe disease is considered as less frequent and severe than that of infantile onset. There are few investigations which show cardiovascular complication of late onset Pompe disease due to the shortage of appropriate disease model...
2015: Molecular Therapy. Methods & Clinical Development
Haodi Wu, Jaecheol Lee, Ludovic G Vincent, Qingtong Wang, Mingxia Gu, Feng Lan, Jared M Churko, Karim I Sallam, Elena Matsa, Arun Sharma, Joseph D Gold, Adam J Engler, Yang K Xiang, Donald M Bers, Joseph C Wu
β-adrenergic signaling pathways mediate key aspects of cardiac function. Its dysregulation is associated with a range of cardiac diseases, including dilated cardiomyopathy (DCM). Previously, we established an iPSC model of familial DCM from patients with a mutation in TNNT2, a sarcomeric protein. Here, we found that the β-adrenergic agonist isoproterenol induced mature β-adrenergic signaling in iPSC-derived cardiomyocytes (iPSC-CMs) but that this pathway was blunted in DCM iPSC-CMs. Although expression levels of several β-adrenergic signaling components were unaltered between control and DCM iPSC-CMs, we found that phosphodiesterases (PDEs) 2A and PDE3A were upregulated in DCM iPSC-CMs and that PDE2A was also upregulated in DCM patient tissue...
July 2, 2015: Cell Stem Cell
Yuelin Zhang, Xiaoting Liang, Songyan Liao, Weixin Wang, Junwen Wang, Xiang Li, Yue Ding, Yingmin Liang, Fei Gao, Mo Yang, Qingling Fu, Aimin Xu, Yuet-Hung Chai, Jia He, Hung-Fat Tse, Qizhou Lian
Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) can protect cardiomyocytes against anthracycline-induced cardiomyopathy (AIC) through paracrine effects. Nonetheless the paracrine effects of human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) on AIC are poorly understood. In vitro studies reveal that doxorubicin (Dox)-induced reactive oxidative stress (ROS) generation and cell apoptosis in neonatal rat cardiomyocytes (NRCMs) are significantly reduced when treated with conditioned medium harvested from BM-MSCs (BM-MSCs-CdM) or iPSC-MSCs (iPSC-MSCs-CdM)...
2015: Scientific Reports
Yee-Ki Lee, Kwong-Man Ng, Hung-Fat Tse
Human inherited cardiomyopathies are one of the major etiologies for heart failure which are associated with significant mortality and morbidity. Unfortunately, there are lack of effective specific therapies for human cardiomyopathies due to the limited understanding on their pathophysiology. Currently, most of the mechanistic studies of human cardiomyopathy are based on transgenic mouse models and invasive collection of limited amount of myocardial biopsy specimen. Disease-specific stem-cells are already available for studying single-gene mutation related diseases, such as cystic fibrosis and fragile X syndrome...
October 2014: Journal of Biomedical Nanotechnology
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