Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy

Ma, Dongrui; Wei, Heming; Lü, Jun; Ho, Shuswen; Zhang, Guangqing; Sun, Xiaoming; Oh, Yingzi; Tan, Suat Hoon; Ng, Mah Lee; Shim, Winston; Wong, Philip; Liew, Reginald

doi:10.1093/eurheartj/ehs226

Cited by 194 publications

(143 citation statements)

References 23 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…Several studies have successfully generated iPSCs from a variety of tissues, including lung (36), and from patients with different diseases (3,8,13,24). The present study demonstrates the generation of iPSCs from lung fibroblasts from non-COPD and COPD patients.…”

Section: Reprogrammed Ipscs Differentiated Toward Functional Fibroblasupporting

confidence: 52%

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells

Basma

Gunji

Iwasawa

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

gramming somatic cells to induced pluripotent stem cells (iPSCs) eliminates many epigenetic modifications that characterize differentiated cells. In this study, we tested whether functional differences between chronic obstructive pulmonary disease (COPD) and non-COPD fibroblasts could be reduced utilizing this approach. Primary fibroblasts from non-COPD and COPD patients were reprogrammed to iPSCs. Reprogrammed iPSCs were positive for oct3/4, nanog, and sox2, formed embryoid bodies in vitro, and induced teratomas in nonobese diabetic/severe combined immunodeficient mice. Reprogrammed iPSCs were then differentiated into fibroblasts (non-COPD-i and COPD-i) and were assessed either functionally by chemotaxis and gel contraction or for gene expression by microarrays and compared with their corresponding primary fibroblasts. Primary COPD fibroblasts contracted three-dimensional collagen gels and migrated toward fibronectin less robustly than non-COPD fibroblasts. In contrast, redifferentiated fibroblasts from iPSCs derived from the non-COPD and COPD fibroblasts were similar in response in both functional assays. Microarray analysis identified 1,881 genes that were differentially expressed between primary COPD and non-COPD fibroblasts, with 605 genes differing by more than twofold. After redifferentiation, 112 genes were differentially expressed between COPD-i and non-COPD-i with only three genes by more than twofold. Similar findings were observed with microRNA (miRNA) expression: 56 miRNAs were differentially expressed between non-COPD and COPD primary cells; after redifferentiation, only 3 miRNAs were differentially expressed between non-COPD-i and COPD-i fibroblasts. Interestingly, of the 605 genes that were differentially expressed between COPD and non-COPD fibroblasts, 293 genes were changed toward control after redifferentiation. In conclusion, functional and epigenetic alterations of COPD fibroblasts can be reprogrammed through formation of iPSCs.

show abstract

Section: Reprogrammed Ipscs Differentiated Toward Functional Fibroblasupporting

confidence: 52%

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells

Basma

Gunji

Iwasawa

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…Importantly, the human heart is composed not only of CMs but also vascular, smooth muscle and epicardial cells; to better mimic its function, we predict that 3D cardiac tissue structures will be widely implemented, especially where interactions between different cell types might underlie the disease. As an example, ARVC has been modelled in hiPSC‐CMs and these are the major cellular players in the cardiac dysfunction in this disease 30, 34, 73; however, the suspected contribution of epicardial cells to fibro‐fatty substitution and the role of inflammation could not so far be studied in two‐dimensional monotypic cultures. The expectation is that complex multicellar structures will be necessary to reflect fully the pathology of the condition.…”

Section: Future Challengesmentioning

confidence: 99%

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

Bellin

Mummery

2016

FEBS Letters

View full text Add to dashboard Cite

Induced pluripotent stem cells (iPSCs) were first generated 10 years ago. Their ability to differentiate into any somatic cell type of the body including cardiomyocytes has already made them a valuable resource for modelling cardiac disease and drug screening. Initially human iPSCs were used mostly to model known disease phenotypes; more recently, and despite a number of recognised shortcomings, they have proven valuable in providing fundamental insights into the mechanisms of inherited heart disease with unknown genetic cause using surprisingly small cohorts. In this review, we summarise the progress made with human iPSCs as cardiac disease models with special focus on the latest mechanistic insights and related challenges. Furthermore, we suggest emerging solutions that will likely move the field forward.

show abstract

“…Moreover, the cardiomyocytes derived from Timothy syndrome patientspecific iPSCs showed irregular contraction, excess Ca 2+ influx, prolonged action potentials, irregular electrical activity, and abnormal calcium transients [229]. Finally, iPSCderived myocardium can be used to reproduce the in vitro characteristics of familial hypertrophic cardiomyopathy [230,231], right ventricular cardiomyopathy [232], and cardiac Na + channel disease [233,234]. These iPSC-derived cell models can provide a physiologically and functionally relevant human cellular context in vitro to reveal the pathogenic mechanism underlying the specific disease phenotype [235].…”

Section: Disease Modelingmentioning

confidence: 99%

Myocardial Reprogramming Medicine: The Development, Application, and Challenge of Induced Pluripotent Stem Cells

Wang

2014

New Journal of Science

View full text Add to dashboard Cite

Induced pluripotent stem cells (iPSCs) can be generated by reprogramming of adult/somatic cells. The somatic cell reprogramming technology offers a promising strategy for patient-specific cardiac regenerative medicine, disease modeling, and drug discovery. iPSCs are an ideal potential option for an autologous cell source, as compared to other stem/progenitor cells, because they can be propagated indefinitely and are able to generate a large number of functional cardiovascular cells. However, there are concerns about the specificity, efficiency, immunogenicity, and safety of iPSCs which are major challenges in current translational studies. In order to bring iPSC technology closer to clinical use, fundamental changes in this technique are required to ensure that therapeutic progenies are functional and nontumorigenic. It is therefore critical to understand and investigate the biology, genetic, and epigenetic mechanisms of iPSCs generation and differentiation. In this spotlight paper the discovery, history, and relative mechanisms of iPSC generation are summarized. The current technological improvements and potential applications are highlighted along with the important challenges and perspectives. Finally, emerging technologies are presented in which improvements to iPSC generation and differentiation approaches might warrant further investigation, such as integration-free approaches, direct reprogramming, and the development of iPSC banking.

show abstract

Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy

Abstract: Patient-specific iPSC-derived cardiomyocytes display key features of ARVC, including reduced cell surface localization of desmosomal proteins and a more adipogenic phenotype.

Cited by 194 publications

References 23 publications

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

Myocardial Reprogramming Medicine: The Development, Application, and Challenge of Induced Pluripotent Stem Cells

Contact Info

Product

Resources

About