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Derivation of ventrical and atrial cardiomyocytes and maturation using biowires

ABSTRACT: Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionise drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line, non-invasive, recording of passive tension, active force, contractile dynamics and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114976 | GEO | 2019/01/24

REPOSITORIES: GEO

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A platform for generation of chamber specific cardiac tissues and disease modelling

Project description:We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.

2018-12-13 | GSE122661 | GEO

Atrial Molecular Asymmetry Precedes the Emergence of Cardiac Septation I

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Engineered co-cultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation [II]

Project description:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs, but patient responses are highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield an immature cellular phenotype and are not easily scalable for high-throughput screening. Here, we report that primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within industry-standard multiwell plates to engineer patterned co-culture (PC) of iPSC-aCMs and atrial fibroblasts that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks versus conventional mono-/co-cultures. PC displayed greater sensitivity for detecting drug efficacy than monocultures, and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a sodium channel mutation. In conclusion, PC is useful to elucidate heterotypic cell signaling in the atria, drug screening, and to model AF.

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Molecular Remodeling of Ion Channels in Human Atrial and Ventricular Myocytes Associated with Ischemic Cardiomyopathy

Project description:Ischemic cardiomyopathy (ICM) leads to congestive heart failure and can cause sudden cardiac death due to arrhythmia. Existing molecular knowledge base of ICM is rudimentary because of lack of specific attribution to cell type and function. This study was designed to investigate cell-specific molecular remodeling of ion channels, exchangers and pumps, which are signaling molecules (SM) involved in electrical, signaling and mechanical functions of the heart. Atrial and ventricular myocytes were isolated by laser-capture microdissection from left atrium and ventricle of healthy and ICM human hearts. SM and their splice variants altered by ICM in cardiomyocytes were identified by splice microarray and validated by RT-PCR. Molecular profiling of ICM-related changes showed that SM in atrial and ventricular myocytes remodel following their unique programs. ICM affected 63 genes in ventricular myocytes and 12 genes in atrial myocytes. Only few of the identified genes were previously linked to human cardiac disfunctions. In our experiments we used 3 healthy hearts rejected from transplantation procedure and explanted ICM hearts from three male patients. Tissue samples were dissected from left ventricle and left atrial appendages. Atrial and ventricular myocytes were laser-capture microdissected from serial 7-8-Âµm thick cryostat sections. Individual cellular total RNA samples were analyzed on custom-built Human Ion Channel Splice Arrays slides (ExonHit) manufactured on the Ion Channel Splice Array sv1.1 platform representing 287 human SM, including 248 alternatively spliced ones in total 1655 splicing events and supplemented with capabilities to recognize connexins and ryanodine receptors.

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Atrial Identity Is Determined by A COUP-TFII Regulatory Network (ChIP-Seq)

2013-06-07 | E-GEOD-46497 | biostudies-arrayexpress

TBX5 overexpression in ventricle

Project description:Understanding how the atrial and ventricular chambers of the heart maintain their distinct identity is a prerequisite for treating chamber-specific diseases. Here, we selectively inactivated the transcription factor Tbx5 in the atrial working myocardium of the neonatal mouse heart to show that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated highly chamber specific genes such as Myl7 and Nppa, and increased expression of ventricular identity genes including Myl2. Using combined single nucleus transcriptome and open chromatin profiling, we assessed genomic accessibility changes underlying the altered atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control atrial cardiomyocytes compared to KO aCMs. 69% of the control-enriched ATAC regions were bound by TBX5, demonstrating a role for TBX5 in maintaining genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. To confirm this hypothesis we analyzed chromatin looping of enhancers marked by H3K27Ac using HiChIP and found 510 chromatin loops that were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 73.7% contained anchors in control-enriched ATAC regions. Conversely, Tbx5 overexpression in the ventricular myocardium drove atrial gene expression. Together, these data demonstrate a role for TBX5 in maintaining the atrial gene expression program by binding to atrial enhancers to preserve tissue-specific chromatin architecture. We highlight this phenomenon at major atrial identity genes including Nppa, Bmp10 and Myl7.

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TBX5 KO multiome

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