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Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs

Published on Dec 26, 2017in Proceedings of the National Academy of Sciences of the United States of America 9.58
· DOI :10.1073/pnas.1708991114
Ming Tao Zhao2
Estimated H-index: 2
(Stanford University),
Haodong Chen11
Estimated H-index: 11
(Stanford University)
+ 15 AuthorsJoseph C. Wu87
Estimated H-index: 87
(Stanford University)
Cite
Abstract
Abstract Patient-specific pluripotent stem cells (PSCs) can be generated via nuclear reprogramming by transcription factors (i.e., induced pluripotent stem cells, iPSCs) or by somatic cell nuclear transfer (SCNT). However, abnormalities and preclinical application of differentiated cells generated by different reprogramming mechanisms have yet to be evaluated. Here we investigated the molecular and functional features, and drug response of cardiomyocytes (PSC-CMs) and endothelial cells (PSC-ECs) derived from genetically relevant sets of human iPSCs, SCNT-derived embryonic stem cells (nt-ESCs), as well as in vitro fertilization embryo-derived ESCs (IVF-ESCs). We found that differentiated cells derived from isogenic iPSCs and nt-ESCs showed comparable lineage gene expression, cellular heterogeneity, physiological properties, and metabolic functions. Genome-wide transcriptome and DNA methylome analysis indicated that iPSC derivatives (iPSC-CMs and iPSC-ECs) were more similar to isogenic nt-ESC counterparts than those derived from IVF-ESCs. Although iPSCs and nt-ESCs shared the same nuclear DNA and yet carried different sources of mitochondrial DNA, CMs derived from iPSC and nt-ESCs could both recapitulate doxorubicin-induced cardiotoxicity and exhibited insignificant differences on reactive oxygen species generation in response to stress condition. We conclude that molecular and functional characteristics of differentiated cells from human PSCs are primarily attributed to the genetic compositions rather than the reprogramming mechanisms (SCNT vs. iPSCs). Therefore, human iPSCs can replace nt-ESCs as alternatives for generating patient-specific differentiated cells for disease modeling and preclinical drug testing.
  • References (41)
  • Citations (14)
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References41
Newest
Published on Nov 10, 2017in Circulation Research 15.86
Ming-Tao Zhao11
Estimated H-index: 11
(Stanford University),
Ning-Yi Shao16
Estimated H-index: 16
(Stanford University)
+ 7 AuthorsJoseph C. Wu87
Estimated H-index: 87
(Stanford University)
Rationale: Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type–specific gene expression in the human heart. Objective: We aimed to decipher the cell type–specific epigenetic signatures in regulatory DNA elements and how they modulate h...
Published on Jun 1, 2017in Nature 43.07
Helena Kilpinen15
Estimated H-index: 15
,
Angela Goncalves10
Estimated H-index: 10
(Wellcome Trust Sanger Institute)
+ 40 AuthorsOliver J. Culley4
Estimated H-index: 4
('KCL': King's College London)
Genetic and phenotypic analysis reveals expression quantitative trait loci in human induced pluripotent stem cell lines associated with cancer and disease.
Published on Sep 1, 2016in Cell Stem Cell 21.46
Masatoshi Nishizawa5
Estimated H-index: 5
(Kyoto University),
Kazuhisa Chonabayashi8
Estimated H-index: 8
(Kyoto University)
+ 15 AuthorsKoji Tanabe18
Estimated H-index: 18
(Kyoto University)
Summary Variation in the differentiation capacity of induced pluripotent stem cells (iPSCs) to specific lineages is a significant concern for their use in clinical applications and disease modeling. To identify factors that affect differentiation capacity, we performed integration analyses between hematopoietic differentiation performance and molecular signatures such as gene expression, DNA methylation, and chromatin status, using 35 human iPSC lines and four ESC lines. Our analyses revealed th...
Published on Jun 2, 2016in JCI insight
Shijun Hu31
Estimated H-index: 31
,
Ming-Tao Zhao11
Estimated H-index: 11
+ 5 AuthorsJoseph C. Wu87
Estimated H-index: 87
Human induced pluripotent stem cells (iPSCs) can be derived from various types of somatic cells by transient overexpression of 4 Yamanaka factors (OCT4, SOX2, C-MYC, and KLF4). Patient-specific iPSC derivatives (e.g., neuronal, cardiac, hepatic, muscular, and endothelial cells [ECs]) hold great promise in drug discovery and regenerative medicine. In this study, we aimed to evaluate whether the cellular origin can affect the differentiation, in vivo behavior, and single-cell gene expression signa...
Published on Jun 1, 2016in Nature Reviews Cardiology 17.42
Ian Y. Chen24
Estimated H-index: 24
,
Elena Matsa19
Estimated H-index: 19
,
Joseph C. Wu87
Estimated H-index: 87
Human induced pluripotent stem cells (hiPSCs) can be differentiated into many cardiovascular cell types, including cardiomyocytes and endothelial cells. hiPSC-derived cardiovascular cells can recapitulate patient-specific and disease-specific phenotypes. In this Review, Chen et al. discuss how hiPSCs can be used as a platform for cardiovascular drug development and disease modelling, and can facilitate individualized therapy in the era of precision medicine.
Published on May 1, 2016in Nature Medicine 30.64
Paul W. Burridge24
Estimated H-index: 24
,
Yong Fuga Li3
Estimated H-index: 3
(Stanford University)
+ 14 AuthorsAntje D. Ebert19
Estimated H-index: 19
(Stanford University)
The chemotherapeutic agent doxorubicin causes cardiac injury in a subset of cancer patients. This variable clinical response to doxorubicin treatment can be recapitulated in vitro by using cardiomyocytes derived from patient-specific induced pluripotent cells.
Published on May 1, 2016in Cell Stem Cell 21.46
Peter Hugo Lodewijk Krijger9
Estimated H-index: 9
(UU: Utrecht University),
Bruno Di Stefano13
Estimated H-index: 13
(UPF: Pompeu Fabra University)
+ 4 AuthorsTanja Graf74
Estimated H-index: 74
(UPF: Pompeu Fabra University)
Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic s...
Published on Mar 1, 2016in Nature Reviews Molecular Cell Biology 43.35
Yishai Avior6
Estimated H-index: 6
,
Ido Sagi7
Estimated H-index: 7
,
Nissim Benvenisty59
Estimated H-index: 59
The use of cultured human pluripotent stem cells (PSCs) to model human diseases has revolutionized the ways in which we study monogenic, multigenic and epigenetic disorders, by overcoming some of the limitations of animal models. PSC-based disease models are generated using various strategies and can be used for the discovery of new drugs and therapies.
Published on Feb 1, 2016in Stem cell reports 5.50
A Kyttällä17
Estimated H-index: 17
(National Institute for Health and Welfare),
Roksana Moraghebi5
Estimated H-index: 5
(Lund University)
+ 15 AuthorsJere Weltner9
Estimated H-index: 9
(UH: University of Helsinki)
Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each oth...
Published on Jan 26, 2016in PLOS Genetics 5.22
Courtney K. Burrows4
Estimated H-index: 4
(U of C: University of Chicago),
Nicholas E. Banovich6
Estimated H-index: 6
(U of C: University of Chicago)
+ 4 AuthorsYoav Gilad58
Estimated H-index: 58
(U of C: University of Chicago)
The advent of induced pluripotent stem cells (iPSCs) revolutionized human genetics by allowing us to generate pluripotent cells from easily accessible somatic tissues. This technology can have immense implications for regenerative medicine, but iPSCs also represent a paradigm shift in the study of complex human phenotypes, including gene regulation and disease. Yet, an unresolved caveat of the iPSC model system is the extent to which reprogrammed iPSCs retain residual phenotypes from their precu...
Cited By14
Newest
Published on Apr 3, 2019in Journal of Biological Engineering 2.67
Jaimeson Veldhuizen (ASU: Arizona State University), Raymond Q. Migrino17
Estimated H-index: 17
,
Mehdi Nikkhah30
Estimated H-index: 30
(ASU: Arizona State University)
In vitro three-dimensional (3D) microengineered tissue models have been the recent focus of pathophysiological studies, particularly in the field of cardiovascular research. These models, as classified by 3D biomimetic tissues within micrometer-scale platforms, enable precise environmental control on the molecular- and cellular-levels to elucidate biological mechanisms of disease progression and enhance efficacy of therapeutic research. Microengineered models also incorporate directed stem cell ...
Published on Dec 1, 2019in Stem Cell Research & Therapy 4.63
Min Xu (Anhui Medical University), Jiacai He (Anhui Medical University)+ 2 AuthorsYuanyin Wang (Anhui Medical University)
Accumulating evidence demonstrates that pre-vascularization of tissue-engineered constructs can significantly enhance their survival and engraftment upon transplantation. Endothelial cells (ECs), the basic component of vasculatures, are indispensable to the entire process of pre-vascularization. However, the source of ECs still poses an issue. Recent studies confirmed that diverse approaches are available in the derivation of ECs for tissue engineering, such as direct isolation of autologous ECs...
Published in Neuron 14.40
Dylan Kwart2
Estimated H-index: 2
(Rockefeller University),
Andrew Gregg1
Estimated H-index: 1
(Rockefeller University)
+ -3 AuthorsMarc Tessier-Lavigne121
Estimated H-index: 121
(Rockefeller University)
Summary Familial Alzheimer’s disease (fAD) results from mutations in the amyloid precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes. Here we leveraged recent advances in induced pluripotent stem cell (iPSC) and CRISPR/Cas9 genome editing technologies to generate a panel of isogenic knockin human iPSC lines carrying APP and/or PSEN1 mutations. Global transcriptomic and translatomic profiling revealed that fAD mutations have overlapping effects on the expression of AD-related and endoc...
Published on Sep 1, 2018in Seminars in Cancer Biology 9.66
Liang Dong1
Estimated H-index: 1
(CityU: City University of Hong Kong),
Xiaoming Lyu8
Estimated H-index: 8
(CityU: City University of Hong Kong)
+ 1 AuthorsMing-Liang He36
Estimated H-index: 36
(CityU: City University of Hong Kong)
Abstract The T-box factors belong to an ancient protein family, which comprises a cluster of evolutionarily-conserved transcription factors that regulate gene expression and that are crucial to embryonic development. T-box transcription factor 3 (Tbx3) is a member of this family, is expressed in some tissues, and is a key regulator in many critical organs, including the heart, mammary gland, and limbs. Overexpression of Tbx3 is associated with a number of cancers, including head and neck squamou...
Published on Dec 1, 2018in The Journal of Allergy and Clinical Immunology
Yuta Kasagi1
Estimated H-index: 1
,
Kara Dods7
Estimated H-index: 7
+ 14 AuthorsJohn W. Tobias32
Estimated H-index: 32
(UPenn: University of Pennsylvania)
Background Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. Objective We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. Methods LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine...
Published on May 1, 2019in Stem cell reports 5.50
Adriana Bozzi , Nazish Sayed13
Estimated H-index: 13
+ 6 AuthorsJoseph C. Wu87
Estimated H-index: 87
Summary Chagas disease (ChD) is one of the most neglected tropical diseases, with cardiomyopathy being the main cause of death in Trypanosoma cruzi -infected patients. As the parasite actively replicates in cardiomyocytes (CMs), the heart remains a key target organ in the pathogenesis of ChD. Here we modeled ChD using human induced pluripotent stem cell-derived CMs (iPSC-CMs) to understand the complex interplay between the parasite and host cells. We showed that iPSC-CMs can get infected with th...
Published on May 24, 2019in bioRxiv
Agnieszka D'Antonio-Chronowska2
Estimated H-index: 2
(UCSD: University of California, San Diego),
Agnieszka D’Antonio-Chronowska (University of California, Berkeley)+ 11 AuthorsHiroko Matsui8
Estimated H-index: 8
(UCSD: University of California, San Diego)
Non-genetic variability in human induced pluripotent stem cell (iPSC) lines impacts their differentiation outcome, limiting their utility for genetic studies and clinical applications. Despite the importance of understanding how non-genetic molecular variability influences iPSC differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we performed 258 directed differentiations of 191 iPSC lines using established protocols to generate iPSC...
Published on Apr 1, 2019in Biomaterials 10.27
Houman Savoji1
Estimated H-index: 1
(U of T: University of Toronto),
Mohammad Hossein Mohammadi6
Estimated H-index: 6
(U of T: University of Toronto)
+ 6 AuthorsMilica Radisic50
Estimated H-index: 50
(U of T: University of Toronto)
Abstract Cardiovascular disease is the leading cause of death worldwide. Although investment in drug discovery and development has been sky-rocketing, the number of approved drugs has been declining. Cardiovascular toxicity due to therapeutic drug use claims the highest incidence and severity of adverse drug reactions in late-stage clinical development. Therefore, to address this issue, new, additional, replacement and combinatorial approaches are needed to fill the gap in effective drug discove...
Published on Mar 11, 2019in Brain Sciences
The most conserved molecular phenotype of Fragile X Syndrome (FXS) is aberrant protein synthesis. This has been validated in a variety of experimental model systems from zebrafish to rats, patient-derived lymphoblasts and fibroblasts. With the advent of personalized medicine paradigms, patient-derived cells and their derivatives are gaining more translational importance, not only to model disease in a dish, but also for biomarker discovery. Here we review past and current practices of measuring ...