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1.
JCI Insight ; 9(11)2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38855866

RESUMO

TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs with either adenoviral expression of WT-TANGO2 or correction of the pathogenic variant using CRISPR editing. Our natural history study in patients with TDD suggests that the intake of multivitamin/B complex greatly diminished the risk of cardiac crises in patients with TDD. In agreement with the clinical findings, we demonstrated that high-dose folate (vitamin B9) virtually abolishes arrhythmias in TDD iPSC-CMs and that folate's effect was blocked by the dihydrofolate reductase inhibitor methotrexate, supporting the need for intracellular folate to mediate antiarrhythmic effects. In summary, data from TDD iPSC-CM models together with clinical observations support the use of B vitamins to mitigate cardiac crises in patients with TDD, providing potentially life-saving treatment strategies during life-threatening events.


Assuntos
Arritmias Cardíacas , Ácido Fólico , Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ácido Fólico/metabolismo , Ácido Fólico/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/genética , Masculino , Feminino , Criança
2.
Elife ; 72018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30561326

RESUMO

Approximately, 30% of embryonic stem cells (ESCs) die after exiting self-renewal, but regulators of this process are not well known. Yap1 is a Hippo pathway transcriptional effector that plays numerous roles in development and cancer. However, its functions in ESC differentiation remain poorly characterized. We first reveal that ESCs lacking Yap1 experience massive cell death upon the exit from self-renewal. We subsequently show that Yap1 contextually protects differentiating, but not self-renewing, ESC from hyperactivation of the apoptotic cascade. Mechanistically, Yap1 strongly activates anti-apoptotic genes via cis-regulatory elements while mildly suppressing pro-apoptotic genes, which moderates the level of mitochondrial priming that occurs during differentiation. Individually modulating the expression of single apoptosis-related genes targeted by Yap1 is sufficient to augment or hinder survival during differentiation. Our demonstration of the context-dependent pro-survival functions of Yap1 during ESC differentiation contributes to our understanding of the balance between survival and death during cell fate changes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/genética , Diferenciação Celular/genética , Células-Tronco Embrionárias Murinas/metabolismo , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular , Autorrenovação Celular , Expressão Gênica , Técnicas de Inativação de Genes , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Mutação , Fosfoproteínas/metabolismo , Proteínas de Sinalização YAP
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