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 America9.58
· DOI :10.1073/pnas.1708991114
Ming-Tao Zhao12
Estimated H-index: 12
(Stanford University),
Haodong Chen12
Estimated H-index: 12
(Stanford University)
+ 15 AuthorsJoseph C. Wu91
Estimated H-index: 91
(Stanford University)
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.
Figures & Tables
  • References (41)
  • Citations (18)
📖 Papers frequently viewed together
13 Authors (Ming-Tao Zhao, ..., Joseph C. Wu)
16.2k Citations
20143.50BMC Genomics
9 Authors (Botao Zhao, ..., Youxin Jin)
13 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Ming-Tao Zhao (Stanford University)H-Index: 12
#2Ningyi Shao (Stanford University)H-Index: 19
Last. Joseph C. Wu (Stanford University)H-Index: 91
view all 10 authors...
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...
2 CitationsSource
#1Helena KilpinenH-Index: 15
#2Antonio Pereira Goncalves (Wellcome Trust Sanger Institute)H-Index: 30
Last. Daniel J. Gaffney (Wellcome Trust Sanger Institute)H-Index: 30
view all 43 authors...
Genetic and phenotypic analysis reveals expression quantitative trait loci in human induced pluripotent stem cell lines associated with cancer and disease.
131 CitationsSource
#1Masatoshi Nishizawa (Kyoto University)H-Index: 5
#2Kazuhisa Chonabayashi (Kyoto University)H-Index: 8
Last. Yoshinori Yoshida (Kyoto University)H-Index: 22
view all 18 authors...
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...
70 CitationsSource
#1Shijun HuH-Index: 31
#2Ming-Tao ZhaoH-Index: 12
Last. Joseph C. WuH-Index: 91
view all 8 authors...
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...
22 CitationsSource
#1Ian Y. ChenH-Index: 25
#2Elena MatsaH-Index: 20
Last. Joseph C. WuH-Index: 91
view all 3 authors...
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.
61 CitationsSource
#1Peter H.L. Krijger (UU: Utrecht University)H-Index: 10
#2Bruno Di Stefano (UPF: Pompeu Fabra University)H-Index: 15
Last. Tanja Graf (UPF: Pompeu Fabra University)H-Index: 75
view all 7 authors...
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...
99 CitationsSource
#1Paul W. BurridgeH-Index: 25
#2Yong Fuga Li (Stanford University)H-Index: 12
Last. Joseph C. Wu (Stanford University)H-Index: 91
view all 17 authors...
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.
183 CitationsSource
#1Yishai AviorH-Index: 6
#2Ido SagiH-Index: 8
Last. Nissim BenvenistyH-Index: 60
view all 3 authors...
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.
248 CitationsSource
#1A Kyttällä (National Institute for Health and Welfare)H-Index: 17
#2Roksana Moraghebi (Lund University)H-Index: 6
Last. Ras Trokovic (UH: University of Helsinki)H-Index: 17
view all 18 authors...
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...
90 CitationsSource
#1Courtney K. Burrows (U of C: University of Chicago)H-Index: 5
#2Nicholas E. Banovich (U of C: University of Chicago)H-Index: 7
Last. Yoav Gilad (U of C: University of Chicago)H-Index: 61
view all 7 authors...
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...
48 CitationsSource
Cited By18
Somatic cell nuclear transfer (SCNT) has shown a wide application in the generation of transgenic animals, protection of endangered animals, and therapeutic cloning. However, the efficiency of SCNT remains very low due to some poorly characterized key factors. Compared with fertilized embryos, somatic donor cells lack some important components of sperm, such as sperm small noncoding RNA (sncRNA) and proteins. Loss of these factors is considered an important reason for the abnormal development of...
#1Qirui Wu (SHU: Shanghai University)
Last. Gong X
view all 8 authors...
The organ-on-a-chip (OOAC) is in the list of top 10 emerging technologies and refers to a physiological organ biomimetic system built on a microfluidic chip. Through a combination of cell biology, engineering, and biomaterial technology, the microenvironment of the chip simulates that of the organ in terms of tissue interfaces and mechanical stimulation. This reflects the structural and functional characteristics of human tissue and can predict response to an array of stimuli including drug resp...
#1David T. Paik (Cardiovascular Institute of the South)H-Index: 6
#2Mark Chandy (Cardiovascular Institute of the South)H-Index: 7
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 91
view all 3 authors...
Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significan...
2 CitationsSource
#1Xing Fang (Soochow University (Suzhou))
#2Shumei Miao (Soochow University (Suzhou))
Last. Wei Lei (Soochow University (Suzhou))H-Index: 12
view all 10 authors...
Abstract MicroRNAs (miRNAs), as a class of naturally occurring RNAs, play important roles in cardiac physiology and pathology. There are many miRNAs that show multifarious expression patterns during cardiomyocyte genesis. Here, we focused on the MIR148A family, which is composed of MIR148A, MIR148B and MIR152, and shares the same seed sequences. The expression levels of all MIR148A family members progressively increased during the differentiation of human embryonic stem cells (hESCs) into cardio...
#1Dylan Kwart (Rockefeller University)H-Index: 3
#2Andrew Gregg (Rockefeller University)H-Index: 2
Last. Marc Tessier-Lavigne (Rockefeller University)H-Index: 124
view all 10 authors...
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...
9 CitationsSource
#1Liang Dong (CityU: City University of Hong Kong)H-Index: 1
#2Xiaoming Lyu (CityU: City University of Hong Kong)H-Index: 8
Last. Ming-Liang He (CityU: City University of Hong Kong)H-Index: 37
view all 4 authors...
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...
#1Min Xu (Anhui Medical University)
#2Jiacai He (Anhui Medical University)
Last. Yuanyin Wang (Anhui Medical University)
view all 5 authors...
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...
#1Yuta KasagiH-Index: 1
#2Kara DodsH-Index: 7
Last. Amanda B. Muir (UPenn: University of Pennsylvania)H-Index: 10
view all 17 authors...
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...
1 CitationsSource
#1Adriana Bozzi (FIOCRUZ: Oswaldo Cruz Foundation)H-Index: 1
#2Nazish Sayed (Cardiovascular Institute of the South)H-Index: 15
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 91
view all 9 authors...
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 the...
1 CitationsSource
#1Agnieszka D'Antonio-Chronowska (University of California, Berkeley)H-Index: 6
#2Margaret K.R. Donovan (University of California, Berkeley)H-Index: 2
Last. Kelly A. Frazer (University of California, Berkeley)H-Index: 56
view all 14 authors...
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...
1 CitationsSource