Abstract:
UNLABELLED:Histone deacetylase (HDAC) inhibitors possess therapeutic potential to reverse aberrant epigenetic changes associated with cancers, neurological diseases, and immune disorders. Unfortunately, clinical studies with some HDAC inhibitors displayed delayed cardiac adverse effects, such as atrial fibrillation and ventricular tachycardia. However, the underlying molecular mechanism(s) of HDAC inhibitor-mediated cardiotoxicity remains poorly understood and is difficult to detect in the early stages of preclinical drug development because of a delayed onset of effects. In the present study, we show for the first time in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) that HDAC inhibitors (dacinostat, panobinostat, vorinostat, entinostat, and tubastatin-a) induce delayed dose-related cardiac dysfunction at therapeutic concentrations associated with cardiac adverse effects in humans. HDAC inhibitor-mediated delayed effects on the beating properties of hiPS-CMs developed after 12 hours by decreasing the beat rate, shortening the field potential duration, and inducing arrhythmic behavior under form of sustained contractions and fibrillation-like patterns. Transcriptional changes that are common between the cardiotoxic HDAC inhibitors but different from noncardiotoxic treatments identified cardiac-specific genes and pathways related to structural and functional changes in cardiomyocytes. Combining the functional data with epigenetic changes in hiPS-CMs allowed us to identify molecular targets that might explain HDAC inhibitor-mediated cardiac adverse effects in humans. Therefore, hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and support identification of better HDAC inhibitors with an improved benefit-risk profile. SIGNIFICANCE:Histone deacetylase (HDAC) inhibitors are a promising class of drugs to treat certain cancers, autoimmune, and neurodegenerative diseases. However, treated patients can experience various cardiac adverse events such as hearth rhythm disorders. This study found that human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) can predict cardiac adverse events in patients caused by HDAC inhibitors. Furthermore, transcriptional changes at the level of gene expression supported the effects on the beating properties of hiPS-CMs and highlight targets that might cause these cardiac adverse effects. hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and to support development of safer HDAC inhibitors.
journal_name
Stem Cells Transl Medjournal_title
Stem cells translational medicineauthors
Kopljar I,Gallacher DJ,De Bondt A,Cougnaud L,Vlaminckx E,Van den Wyngaert I,Lu HRdoi
10.5966/sctm.2015-0279subject
Has Abstractpub_date
2016-05-01 00:00:00pages
602-12issue
5eissn
2157-6564issn
2157-6580pii
sctm.2015-0279journal_volume
5pub_type
杂志文章abstract::Burns not only destroy the barrier function of the skin but also alter the perceptions of pain, temperature, and touch. Different strategies have been developed over the years to cover deep and extensive burns with the ultimate goal of regenerating the barrier function of the epidermis while recovering an acceptable a...
journal_title:Stem cells translational medicine
pub_type: 杂志文章,评审
doi:10.5966/sctm.2012-0181
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abstract::Owing to the rapid progress in stem cell research (SCR) and regenerative medicine (RM), society's expectation and interest in these fields are increasing. For effective communication on issues concerning SCR and RM, surveys for understanding the interests of stakeholders is essential. For this purpose, we conducted a ...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
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abstract:UNLABELLED:Human cord blood (CB)-derived hematopoietic stem cells (HSCs) are an interesting source for HSC transplantation. However, the number of collected CB-HSCs is often too low for one transplantation; therefore, ex vivo expansion of CB-HSCs is desirable. Current expansion protocols are based on the use of cytokin...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0284
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abstract::Peripheral nerve injury presents significant therapeutic challenges for recovery of motor and sensory function in patients. Different clinical approaches exist but to date there has been no consensus on the most effective method of treatment. Here, we investigate a novel approach to peripheral nerve repair using olfac...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.16-0420
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.19-0106
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abstract::Osteoarthritic and other types of articular cartilage defects never heal on their own. Medicinal and surgical approaches are often ineffective, and the supply of autologous chondrocytes for tissue engineering is very limited. Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) h...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0015
更新日期:2014-10-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章,随机对照试验
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更新日期:2012-03-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
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更新日期:2019-08-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2016-0040
更新日期:2017-01-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.17-0149
更新日期:2018-01-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2012-0025
更新日期:2012-07-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.1002/sctm.16-0470
更新日期:2017-09-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2012-0041
更新日期:2013-01-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2015-0289
更新日期:2017-02-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2012-0137
更新日期:2014-02-01 00:00:00
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journal_title:Stem cells translational medicine
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1002/sctm.20-0227
更新日期:2021-02-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
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更新日期:2018-12-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2013-0027
更新日期:2013-09-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2014-0287
更新日期:2015-07-01 00:00:00
abstract::There has been considerable progress in obtaining engraftable embryonic stem (ES) cell-derived midbrain dopamine neurons for cell replacement therapy in models of Parkinson's disease; however, limited integration and striatal reinnervation of ES-derived grafts remain a major challenge for future clinical translation. ...
journal_title:Stem cells translational medicine
pub_type: 杂志文章
doi:10.5966/sctm.2013-0084
更新日期:2014-01-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 杂志文章
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更新日期:2019-01-01 00:00:00
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journal_title:Stem cells translational medicine
pub_type: 临床试验,杂志文章
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更新日期:2016-05-01 00:00:00