Patient-Specific Induced Pluripotent Stem Cells Implicate Intrinsic Impaired Contractility in Hypoplastic Left Heart Syndrome

Paige, Sharon L.; Galdos, Francisco X; Lee, Soah; Chin, Elizabeth T; Ranjbarvaziri, Sara; Feyen, Dries; Darsha, Adrija; Xu, Sidra; Ryan, Julia; Beck, Aimee; Qureshi, Muhammad Yasir; Miao, Yifei; Gu, Mingxia; Bernstein, Daniel; Nelson, T. J. N.; Mercola, Mark; Rabinovitch, Marlene; Ashley, Euan A.; Parikh, Victoria N.; Wu, Sean M.

doi:10.1161/circulationaha.119.045317

Cited by 33 publications

(33 citation statements)

References 5 publications

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“…This innovative study focused on mutations in a transcription factor (ETS) and a chromatin remodeler (CHD7), identifying a large, downstream gene network that was differentially expressed in control vs. HLHS endocardial cells ( 15 ). Another study by Paige et al observed a drastic impairment in contractility of HLHS iPSC-CMs in addition to associated changes in gene expression that significantly overlapped prior studies of human heart failure ( 67 ). Using iPSC-CMs they discovered 3 gene sets that were identified as molecular coordinators in heart failure (i.e., local, pathway, and central coordinators) ( 67 ).…”

Section: Use Of Ipscs To Model Chdmentioning

confidence: 70%

“…Another study by Paige et al observed a drastic impairment in contractility of HLHS iPSC-CMs in addition to associated changes in gene expression that significantly overlapped prior studies of human heart failure ( 67 ). Using iPSC-CMs they discovered 3 gene sets that were identified as molecular coordinators in heart failure (i.e., local, pathway, and central coordinators) ( 67 ). Finally, Kitani et al provided genome-wide transcriptomic profiles of iPSC-CMs that were established from 5 patients with single ventricle disease (SVD) (including 1 HLHS, 2 tricuspid atresia, 1 double-outlet right ventricle, 1 double-inlet left ventricle) vs. five patients with non-syndromic ToF ( 5 ).…”

Section: Use Of Ipscs To Model Chdmentioning

confidence: 70%

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Race and Genetics in Congenital Heart Disease: Application of iPSCs, Omics, and Machine Learning Technologies

Mullen

Zhang

Romfh

et al. 2021

Front. Cardiovasc. Med.

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Congenital heart disease (CHD) is a multifaceted cardiovascular anomaly that occurs when there are structural abnormalities in the heart before birth. Although various risk factors are known to influence the development of this disease, a full comprehension of the etiology and treatment for different patient populations remains elusive. For instance, racial minorities are disproportionally affected by this disease and typically have worse prognosis, possibly due to environmental and genetic disparities. Although research into CHD has highlighted a wide range of causal factors, the reasons for these differences seen in different patient populations are not fully known. Cardiovascular disease modeling using induced pluripotent stem cells (iPSCs) is a novel approach for investigating possible genetic variants in CHD that may be race specific, making it a valuable tool to help solve the mystery of higher incidence and mortality rates among minorities. Herein, we first review the prevalence, risk factors, and genetics of CHD and then discuss the use of iPSCs, omics, and machine learning technologies to investigate the etiology of CHD and its connection to racial disparities. We also explore the translational potential of iPSC-based disease modeling combined with genome editing and high throughput drug screening platforms.

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Section: Use Of Ipscs To Model Chdmentioning

confidence: 70%

Section: Use Of Ipscs To Model Chdmentioning

confidence: 70%

Race and Genetics in Congenital Heart Disease: Application of iPSCs, Omics, and Machine Learning Technologies

Mullen

Zhang

Romfh

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…Single-cell RNA-seq analysis of human and mouse hearts has provided unprecedented resources on the trajectory of cardiac development in vivo at single-cell resolution and revealed a blueprint on how normal cell fate determination is altered under genetic perturbation and pathological conditions such as CHD ( Cui et al, 2019 ; De Soysa et al, 2019 ; Litvinukova et al, 2020 ; Paik et al, 2020 ). Single-cell transcriptional profiling of healthy and diseased iPSCs during cardiac differentiation would decipher how a given genetic variant affects cardiac differentiation and developmental trajectories, and uncover new molecular insights in the pathogenesis of CHD ( Churko et al, 2018 ; Kathiriya et al, 2020 ; Lam et al, 2020 ; Miao et al, 2020 ; Paige et al, 2020 ). As heart development is dependent on interaction among multiple cell types in the embryo, cardiac organoids and 3D bio-printing may serve as another tier of disease modeling using patient iPSCs ( Lee et al, 2019 ; Nugraha et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

Lin

McBride

Garg

et al. 2021

Front. Cell Dev. Biol.

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Congenital heart disease (CHD) is the most common cause of infant death associated with birth defects. Recent next-generation genome sequencing has uncovered novel genetic etiologies of CHD, from inherited and de novo variants to non-coding genetic variants. The next phase of understanding the genetic contributors of CHD will be the functional illustration and validation of this genome sequencing data in cellular and animal model systems. Human induced pluripotent stem cells (iPSCs) have opened up new horizons to investigate genetic mechanisms of CHD using clinically relevant and patient-specific cardiac cells such as cardiomyocytes, endothelial/endocardial cells, cardiac fibroblasts and vascular smooth muscle cells. Using cutting-edge CRISPR/Cas9 genome editing tools, a given genetic variant can be corrected in diseased iPSCs and introduced to healthy iPSCs to define the pathogenicity of the variant and molecular basis of CHD. In this review, we discuss the recent progress in genetics of CHD deciphered by large-scale genome sequencing and explore how genome-edited patient iPSCs are poised to decode the genetic etiologies of CHD by coupling with single-cell genomics and organoid technologies.

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“…An alternative strategy entails in vitro disease modeling using induced pluripotent stem cells (iPSC) and their differentiated derivatives such as cardiomyocytes (iPSC-CM), endothelial/endocardial cells, and other cell types. While this has been successfully deployed for investigating HLHS disease mechanisms (Gaber et al, 2013; Hrstka et al, 2017; Jiang et al, 2014a; Kobayashi et al, 2014; Miao et al, 2020; Paige et al, 2020), no studies have explored the possibility of using iPSC-CM to model disease outcome. Particularly compelling is the question as to why only some HLHS patients develop early-HF even with the same surgical palliation, and what might be the underlying cause for HF.…”

Section: Introductionmentioning

confidence: 99%

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Jin

et al. 2021

Preprint

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Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.

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Patient-Specific Induced Pluripotent Stem Cells Implicate Intrinsic Impaired Contractility in Hypoplastic Left Heart Syndrome

Cited by 33 publications

References 5 publications

Race and Genetics in Congenital Heart Disease: Application of iPSCs, Omics, and Machine Learning Technologies

Race and Genetics in Congenital Heart Disease: Application of iPSCs, Omics, and Machine Learning Technologies

Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

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