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| Open AccessCD24 tracks divergent pluripotent states in mouse and human cells
Characterizing the cellular stages that lead to induced reprogramming is of much interest and cell surface markers could offer unique advantages for this. Here the authors use surface proteomics and discover CD24 as a marker that tracks reprogramming-responsive cells and enables the analysis and enrichment of transgene-dependent and -independent induced pluriopotent stem cells.
- Nika Shakiba
- , Carl A. White
- & Peter W Zandstra
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Article
| Open AccessMitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling
The pluripotent state of mouse embryonic stem cells (mESCs) is regulated by extrinsic and intrinsic signals but the underlying mechanisms are not completely understood. Here the authors show that the E3 ligase, March5, contributes to the maintenance of the pluripotent state in mESCs via suppression of ERK activation.
- Hao Gu
- , Qidong Li
- & Mian Wu
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Article
| Open AccessProteins that bind regulatory regions identified by histone modification chromatin immunoprecipitations and mass spectrometry
The protein factors that bind to regulatory regions in the genome have not been systematically mapped. Here the authors performed chromatin immunoprecipitations for histone modifications associated with promoters, enhancers or heterochromatin in mouse embryonic stem cells and assigned a genome location to many factors important for pluripotency.
- Erik Engelen
- , Johannes H. Brandsma
- & Raymond A. Poot
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| Open AccessReinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency
LIF/STAT3 signalling characterizes naive pluripotency in mouse embryonic stem cells (ESCs), but whether this pathway can sustain a similar state in human cells is not completely understood. Here the authors show that LIF stimulation and enhancement of STAT3 activity allow human ESCs to escape from FGF2 dependency and facilitates their entry into a naive-like state of pluripotency.
- Hongwei Chen
- , Irène Aksoy
- & Pierre Savatier
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Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells
Applications of human pluripotent stem cells (hPSCs) for disease modelling or cell therapy are hindered by low efficiency and heterogeneity of target cell types differentiated from hPSCs, such as motor neurons (MNs). Here the authors develop a method to derive highly pure motor neuron progenitor populations from human embryonic and induced pluripotent stem cells that yield functional MNs.
- Zhong-Wei Du
- , Hong Chen
- & Su-Chun Zhang
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Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells
Mice can be generated from induced pluripotent stem cells (iPSCs) but the impact of accumulated mutations on the developmental potential of the cells remains to be determined. Here the authors show that mice generated from iPSCs tolerate the accumulation of somatic mutations for up to six generations, but their viability decreased with increasing generations.
- Shuai Gao
- , Caihong Zheng
- & Shaorong Gao
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| Open AccessCollaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways
Improving the efficiency of reprogramming of somatic cells to induced pluripotent stem cells is of major interest. Here, the authors combine ascorbic acid and 2i (MAP kinase and GSK inhibitors) conditions and show increased efficiency and synchronicity in the reprogramming of fibroblasts and partially reprogrammed cells, and study epigenetic effectors and signalling pathways responsible for this effect.
- Khoa A. Tran
- , Steven A. Jackson
- & Rupa Sridharan
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| Open AccessDppa3 expression is critical for generation of fully reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting
Reprogramming of mouse somatic cells into iPSCs often generates pre-iPSCs, low-grade iPSCs that show abnormal Dlk1-Dio3 imprinting, and fully reprogrammed, high-grade iPSCs. Here, the authors show that germ-cell marker Dppa3 enhances reprogramming kinetics, critical for the maintenance of Dlk1-Dio3 imprinting and generation of fully reprogrammed iPSCs.
- Xingbo Xu
- , Lukasz Smorag
- & D. V. Krishna Pantakani
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| Open AccessHuman iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects spinal cord motor neurons. Here the authors use induced pluripotent stem cell-derived motor neurons obtained from patients with ALS-linked mutations, and find functional deficits resulting from a progressive decrease in voltage-activated Na+ and K+currents that occur in the absence of cell death.
- Anna-Claire Devlin
- , Karen Burr
- & Gareth B. Miles
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Small RNA changes en route to distinct cellular states of induced pluripotency
Somatic cell reprogramming can induce distinct pluripotent states. Here the authors perform time-resolved small RNA expression profiling during the reprogramming of mouse embryonic fibroblasts and observe that distinct miRNA milieus characterise alternate states of pluripotency.
- Jennifer L. Clancy
- , Hardip R. Patel
- & Thomas Preiss
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Proteome adaptation in cell reprogramming proceeds via distinct transcriptional networks
During somatic cell reprogramming, the cell transits through intermediate states. Here, the authors perform an in-depth quantitative proteomic analysis of the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells and observe two waves of proteome reorganisation.
- Marco Benevento
- , Peter D. Tonge
- & Albert J. R. Heck
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Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states
Molecular and functional differences between induced pluripotent stem cells (iPSCs) derived from distinct cell types have been described. Here the authors show, by comparing human iPSCs derived from fibroblasts or cord blood, that the competence in activating developmental genes upon differentiation is influenced by the donor cell of origin.
- Jong-Hee Lee
- , Jung Bok Lee
- & Mickie Bhatia
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| Open AccessTargeted and genome-wide sequencing reveal single nucleotide variations impacting specificity of Cas9 in human stem cells
The microbial RNA-guided CRISPR/Cas9 system has robust genome-editing activities, but the off-target effects of the Cas9 nuclease have only recently begun to be analysed. Here the authors provide evidence for high specificity of the Cas9 nuclease on targeting of the Tafazzin gene in human-induced pluripotent stem cells and demonstrate the impact of single-nucleotide variations of the human genome on Cas9 specificity.
- Luhan Yang
- , Dennis Grishin
- & George Church
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Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells
Trisomy 12 is the most frequent chromosomal abnormality detected in cultures of human pluripotent stem cells. Here the authors show that human pluripotent stem cells carrying this abnormality exhibit gene expression profiles more similar to those of germ cell tumours, and give rise to more aggressive teratomas.
- Uri Ben-David
- , Gal Arad
- & Juan Carlos Biancotti
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| Open AccessRole of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells
Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.
- Chen Chen
- , Peng Jiang
- & Wenbin Deng
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Direct induction of haematoendothelial programs in human pluripotent stem cells by transcriptional regulators
The haemogenic endothelium gives rise to haematopoietic cells including haematopoietic stem cells. Here, the authors show that the transduction of two combinations of transcription factors into human pluripotent stem cells convert these into haemogenic endothelial cells with distinct lineage potentials.
- Irina Elcheva
- , Vera Brok-Volchanskaya
- & Igor Slukvin
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Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs
Fanconi anaemia (FA) is a genetic disease associated with low levels of blood stem cells. Here Liu et al.report an improved method to generate genetically corrected induced pluripotent stem cells from an FA patient, and perform a screening to identify drugs that improve their differentiation into blood stem cells.
- Guang-Hui Liu
- , Keiichiro Suzuki
- & Juan Carlos Izpisua Belmonte
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Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs
Induced pluripotent stem cells (iPSCs) hold great potential for modelling human developmental processes and diseases. Here the authors induce human iPSCs to spontaneously form fully laminated three-dimensional retinal tissue containing functional photoreceptor cells.
- Xiufeng Zhong
- , Christian Gutierrez
- & M. Valeria Canto-Soler
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Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance
Transplantation of mouse-induced pluripotent stem cells (iPSCs), but not of iPSC-derived terminally differentiated cells, triggers a T-cell-dependent immune response. Here the authors show that iPSC-derived endothelial cells are accepted by self-tolerance mechanisms similar to autologous endothelial cells.
- Patricia .E de Almeida
- , Everett H. Meyer
- & Joseph C. Wu
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High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1
Motor neurons generated from human pluripotent stem cells are used for disease modelling and drug screening. Here the authors present a protocol for efficient generation of mature spinal motor neurons from human pluripotent stem cells by precisely timing the application of the neural patterning molecule retinoic acid.
- Qiuhao Qu
- , Dong Li
- & Fei Wang
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Foxd1 is a mediator and indicator of the cell reprogramming process
The forkhead box transcription factor Foxo1 is required for the maintenance of pluripotency in human embryonic stem cells. Here Koga et al.show that expression of another forkhead box transcription factor, Foxd1, promotes and indicates successful reprogramming of mouse embryonic fibroblasts.
- Makito Koga
- , Mitsuhiro Matsuda
- & Miki Ebisuya
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Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells
The hair follicle bulge contains epithelial stem cells that contribute to follicle formation during each hair cycle. Here the authors differentiate human induced pluripotent stem cells into folliculogenic epithelial stem cells, which can produce all hair follicle lineages including a stem cell population.
- Ruifeng Yang
- , Ying Zheng
- & Xiaowei Xu
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iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF
The neurotrophic cytokine leukaemia inhibitory factor (LIF) prevents oligodendrocyte death in animal models of multiple sclerosis. Here, Laterza et al. show that secretion of LIF from transplanted iPSC-derived neural progenitor cells has a therapeutic effect in a mouse model of multiple sclerosis.
- Cecilia Laterza
- , Arianna Merlini
- & Gianvito Martino
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MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation
MBNL and FOX splicing factors are known to have a role in the differentiation of muscle and the nervous system during development. In this study, the authors show that MBNL1 and RBFOX2 regulate alternative splicing of genes that are required specifically for late mesoderm differentiation.
- Julian P. Venables
- , Laure Lapasset
- & Jamal Tazi
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Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells
Artificial heart tissue may find application in novel therapies of cardiac disease in the future. Here, Lu et al. take a step towards the creation of personalized heart tissue by repopulating decellularized mouse hearts with cells derived from human induced pluripotent stem cells.
- Tung-Ying Lu
- , Bo Lin
- & Lei Yang
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The p53–PUMA axis suppresses iPSC generation
Inhibition of the p53–p21 axis increases reprogramming efficiency of somatic cells into induced pluripotent stem cells (iPSCs). Here the authors show that depletion of the pro-apoptotic factor PUMA, acting downstream of p53, increases reprogramming efficiency, providing new insights into the roles of p53 in reprogramming.
- Yanxin Li
- , Haizhong Feng
- & Tao Cheng
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Immunologic and chemical targeting of the tight-junction protein Claudin-6 eliminates tumorigenic human pluripotent stem cells
The potential tumorigenicity of human pluripotent stem cells (hPSCs) limits their application in cell therapies. Ben-David et al.identify the tight-junction protein Claudin-6 as a cell-surface marker of hPSCs, and demonstrate three Claudin-6-based strategies to remove tumorigenic hPSCs from mixed cell cultures.
- Uri Ben-David
- , Neta Nudel
- & Nissim Benvenisty
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Zscan4 restores the developmental potency of embryonic stem cells
Mouse embryonic stem cells gradually lose their developmental potency in long-term culture. Here the authors show that their deteriorating developmental potency can be restored by transient activation of the Zscan4gene.
- Tomokazu Amano
- , Tetsuya Hirata
- & Minoru S. H. Ko
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TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells
TRF-1 is a telomere-binding protein that protects chromosome ends from degradation. Schneider and colleagues show that TRF1 is a marker of adult stem cell compartments and of induced pluripotent stem cells, and that TRF1 is essential for the induction and maintenance of pluripotency.
- Ralph P. Schneider
- , Ianire Garrobo
- & Maria A. Blasco
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Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells
Stem cells have raised hopes of developing regenerative therapies of renal disease. Here, Osafune et al.provide a protocol for the differentiation of induced human pluripotent stem cells into renal lineages with the capacity to form tubular renal structures in mice.
- Shin-Ichi Mae
- , Akemi Shono
- & Kenji Osafune
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Analysis of protein-coding mutations in hiPSCs and their possible role during somatic cell reprogramming
Recent studies have shown that human induced pluripotent stem cells contain point mutations in coding regions, but the functional significance of these mutations is unclear. Here the authors provide evidence that these mutations are unlikely to confer a selective advantage for reprogramming.
- Sergio Ruiz
- , Athurva Gore
- & Juan Carlos Izpisua Belmonte
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The RB family is required for the self-renewal and survival of human embryonic stem cells
While human embryonic stem cells (ESC) hold great therapeutic promise, many aspects of their basic biology remain poorly understood. Conklin et al.show that too much or too little activation of RB family proteins is detrimental to human ESC populations and identify unique cell cycle regulatory networks in these cells.
- Jamie F. Conklin
- , Julie Baker
- & Julien Sage
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| Open AccessLaminin E8 fragments support efficient adhesion and expansion of dissociated human pluripotent stem cells
The use of animal products as culture substrates for human embryonic stem cell and induced pluripotent stem cell culture raises numerous safety concerns in a therapeutic setting. Miyazaki et al.. show that minimal fragments of human laminins provide a more effective support for the culture of these cell types.
- Takamichi Miyazaki
- , Sugiko Futaki
- & Eihachiro Kawase
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| Open AccessA kinase inhibitor screen identifies small-molecule enhancers of reprogramming and iPS cell generation
The efficiency of reprogramming somatic cells to induced pluripotent stem cells is low. To enhance reprogramming efficiency, Li and Rana used a chemical screen and identified several kinase inhibitors that enhance reprogramming, and show that blocking Aurora A, p38 and inositiol triphosphate 3-kinase signalling is important for this process.
- Zhonghan Li
- & Tariq M. Rana
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Reprogramming within hours following nuclear transfer into mouse but not human zygotes
The generation of human cell lines using somatic cell nuclear transfer has been difficult to achieve. In this study, Egliet al. show that while mouse eggs reprogram somatic cells within hours, human eggs arrest after nuclear transfer which may be due to a lack of genome transcription.
- Dieter Egli
- , Alice E. Chen
- & Kevin Eggan
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Non-muscle myosin II regulates survival threshold of pluripotent stem cells
When cultured as single cells, embryonic stem cells have low viability. Here, blebbistatin, a non-muscle myosin II inhibitor, is shown to enhance the cloning efficiency, viability and adhesion of both human embryonic stem cells and human induced pluripotent stem cellsin vitro.
- Andrea Walker
- , Hua Su
- & Noboru Sato