Direct Cardiac Reprogramming: Progress and Promise

Engel, J; Ardehali, Reza

doi:10.1155/2018/1435746

Cited by 19 publications

(18 citation statements)

References 64 publications

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“…We next examined skin fibroblasts because these can be obtained via minimally invasive means and can be reprogrammed into other cell types. 41 , 71 , 72 , 73 We obtained transcriptomes from fibroblasts from 26 individuals, and we additionally considered the GTEx control data for immortalized fibroblasts. Our skin fibroblasts (passage 1–4) clustered together in a similar way as immortalized fibroblasts, though their expression profiles overlapped incompletely ( Figure 2 A).…”

Section: Resultsmentioning

confidence: 99%

Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

Gonorazky

Naumenko

Ramani

et al. 2019

The American Journal of Human Genetics

207

225

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Gene-panel and whole-exome analyses are now standard methodologies for mutation detection in Mendelian disease. However, the diagnostic yield achieved is at best 50%, leaving the genetic basis for disease unsolved in many individuals. New approaches are thus needed to narrow the diagnostic gap. Whole-genome sequencing is one potential strategy, but it currently has variant-interpretation challenges, particularly for non-coding changes. In this study we focus on transcriptome analysis, specifically total RNA sequencing (RNA-seq), by using monogenetic neuromuscular disorders as proof of principle. We examined a cohort of 25 exome and/or panel “negative” cases and provided genetic resolution in 36% (9/25). Causative mutations were identified in coding and non-coding exons, as well as in intronic regions, and the mutational pathomechanisms included transcriptional repression, exon skipping, and intron inclusion. We address a key barrier of transcriptome-based diagnostics: the need for source material with disease-representative expression patterns. We establish that blood-based RNA-seq is not adequate for neuromuscular diagnostics, whereas myotubes generated by transdifferentiation from an individual’s fibroblasts accurately reflect the muscle transcriptome and faithfully reveal disease-causing mutations. Our work confirms that RNA-seq can greatly improve diagnostic yield in genetically unresolved cases of Mendelian disease, defines strengths and challenges of the technology, and demonstrates the suitability of cell models for RNA-based diagnostics. Our data set the stage for development of RNA-seq as a powerful clinical diagnostic tool that can be applied to the large population of individuals with undiagnosed, rare diseases and provide a framework for establishing minimally invasive strategies for doing so.

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Section: Resultsmentioning

confidence: 99%

Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

Gonorazky

Naumenko

Ramani

et al. 2019

The American Journal of Human Genetics

207

225

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“…An alternative is direct reprogramming which aims to convert resident cardiac fibroblasts into cardiomyocytes in situ. Several small molecules, transcription factors, and ncRNAs have been identified and used to mediate the direct trans-differentiation [ 32 , 65 ]. This evidence, however, is still not sufficiently robust to determine whether this approach can generate the large number of cardiomyocytes needed to replenish the lost myocardium.…”

Section: Cardiomyocyte Proliferation and Heart Regenerationmentioning

confidence: 99%

Non-coding RNAs: emerging players in cardiomyocyte proliferation and cardiac regeneration

2020

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Soon after birth, the regenerative capacity of the mammalian heart is lost, cardiomyocytes withdraw from the cell cycle and demonstrate a minimal proliferation rate. Despite improved treatment and reperfusion strategies, the uncompensated cardiomyocyte loss during injury and disease results in cardiac remodeling and subsequent heart failure. The promising field of regenerative medicine aims to restore both the structure and function of damaged tissue through modulation of cellular processes and regulatory mechanisms involved in cardiac cell cycle arrest to boost cardiomyocyte proliferation. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are functional RNA molecules with no protein-coding function that have been reported to engage in cardiac regeneration and repair. In this review, we summarize the current understanding of both the biological functions and molecular mechanisms of ncRNAs involved in cardiomyocyte proliferation. Furthermore, we discuss their impact on the structure and contractile function of the heart in health and disease and their application for therapeutic interventions.

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“…More information on the currently available protocols to generate PSC-derived CMs and criteria to distinguish the different subtypes of PSC-derived CMs can be found in some recent reviews (116,127,(132)(133)(134). An alternative strategy to generate CMs from non-CMs is through the direct cardiomyogenic reprogramming of fibroblasts by (cardiomyogenic) transcription factors, miRNAs or small molecules (135,136). However, thus far, the reprogramming efficiencies are low and the resulting so-called induced CM-like cells (iCMs) are rather immature and comprise a mixture of different CM subtypes, limiting their suitability for cardiac disease modeling.…”

Section: (Human) Psc-derived Atrial(-like) Cmsmentioning

confidence: 99%

Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

Gorp

Trines

Pijnappels

et al. 2020

Front. Cardiovasc. Med.

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Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice with a large socioeconomic impact due to its associated morbidity, mortality, reduction in quality of life and health care costs. Currently, antiarrhythmic drug therapy is the first line of treatment for most symptomatic AF patients, despite its limited efficacy, the risk of inducing potentially life-threating ventricular tachyarrhythmias as well as other side effects. Alternative, in-hospital treatment modalities consisting of electrical cardioversion and invasive catheter ablation improve patients' symptoms, but often have to be repeated and are still associated with serious complications and only suitable for specific subgroups of AF patients. The development and progression of AF generally results from the interplay of multiple disease pathways and is accompanied by structural and functional (e.g., electrical) tissue remodeling. Rational development of novel treatment modalities for AF, with its many different etiologies, requires a comprehensive insight into the complex pathophysiological mechanisms. Monolayers of atrial cells represent a simplified surrogate of atrial tissue well-suited to investigate atrial arrhythmia mechanisms, since they can easily be used in a standardized, systematic and controllable manner to study the role of specific pathways and processes in the genesis, perpetuation and termination of atrial arrhythmias. In this review, we provide an overview of the currently available two-and three-dimensional multicellular in vitro systems for investigating the initiation, maintenance and termination of atrial arrhythmias and AF. This encompasses cultures of primary (animal-derived) atrial cardiomyocytes (CMs), pluripotent stem cell-derived atrial-like CMs and (conditionally) immortalized atrial CMs. The strengths and weaknesses of each of these model systems for studying atrial arrhythmias will be discussed as well as their implications for future studies.

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Direct Cardiac Reprogramming: Progress and Promise

Cited by 19 publications

References 64 publications

Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

Non-coding RNAs: emerging players in cardiomyocyte proliferation and cardiac regeneration

Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

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