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| Open AccessSelf-patterning of human stem cells into post-implantation lineages
Human pluripotent stem cells can be triggered to self-organize into structures recapitulating early human post-implantation embryonic development.
- Monique Pedroza
- , Seher Ipek Gassaloglu
- & Berna Sozen
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Article
| Open AccessEmbryo model completes gastrulation to neurulation and organogenesis
Synthetic mouse embryos assembled from embryonic stem cells, trophoblast stem cells and induced extraembryonic endoderm stem cells closely recapitulate the development of wild-type and mutant natural mouse embryos up to embryonic day 8.5.
- Gianluca Amadei
- , Charlotte E. Handford
- & Magdalena Zernicka-Goetz
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Article |
Induction of mouse totipotent stem cells by a defined chemical cocktail
Under chemically defined conditions, mouse pluripotent stem cells can be induced to closely resemble authentic totipotent stem cells that can differentiate to both embryonic and extraembryonic lineages.
- Yanyan Hu
- , Yuanyuan Yang
- & Sheng Ding
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Article |
Spatial profiling of early primate gastrulation in utero
3D transcriptomes reveal the molecular code of lineage specification in the primate embryo and provide an in vivo reference to decipher human development.
- Sophie Bergmann
- , Christopher A. Penfold
- & Thorsten E. Boroviak
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Article |
Rolling back human pluripotent stem cells to an eight-cell embryo-like stage
The development of a transgene-free, rapid and controllable method for producing eight-cell-like cells from human pluripotent stem cells provides a valuable resource to study early human embryogenesis.
- Md. Abdul Mazid
- , Carl Ward
- & Miguel A. Esteban
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Article |
A non-canonical tricarboxylic acid cycle underlies cellular identity
A non-canonical tricarboxylic acid cycle is required for changes in cell state.
- Paige K. Arnold
- , Benjamin T. Jackson
- & Lydia W. S. Finley
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Article |
Brahma safeguards canalization of cardiac mesoderm differentiation
The BAF chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells.
- Swetansu K. Hota
- , Kavitha S. Rao
- & Benoit G. Bruneau
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Article
| Open AccessHuman blastoids model blastocyst development and implantation
Blastoids derived from naive PXGL-cultured human pluripotent stem cells in which Hippo, TGF-β and ERK pathways are inhibited closely recapitulate aspects of blastocyst development, form cells resembling blastocyst-stage cells and thus provide a model system for implantation and development studies.
- Harunobu Kagawa
- , Alok Javali
- & Nicolas Rivron
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Article |
Global miRNA dosage control of embryonic germ layer specification
The levels of microRNAs in mouse and human cells control lipid metabolism and germ cell specification during development.
- Yingzi Cui
- , Xuehui Lyu
- & Richard I. Gregory
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Article |
Blastocyst-like structures generated from human pluripotent stem cells
An in vitro culture strategy enables the generation of blastocyst-like structures termed human blastoids from naive human pluripotent stem cells, providing a model for studying human embryogenesis.
- Leqian Yu
- , Yulei Wei
- & Jun Wu
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Article |
The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity
N6-methyladenosine RNA and its reader YTHDC1 serve as a bridge to silencing retrotransposons through the RNA derived from these retrotransposons in mouse ES cells.
- Jiadong Liu
- , Mingwei Gao
- & Jiekai Chen
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Article |
TRF2-mediated telomere protection is dispensable in pluripotent stem cells
Depletion of TRF2—an essential mediator of telomere protection in most mammalian cells—in mouse embryonic stem cells activates a compensatory transcriptional program that renders TRF2 dispensable for their survival and proliferation.
- Marta Markiewicz-Potoczny
- , Anastasia Lobanova
- & Eros Lazzerini Denchi
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Article |
An in vitro model of early anteroposterior organization during human development
Human gastruloids—three-dimensional aggregates derived from human embryonic stem cells—show features of human embryos at around 19–21 days, and provide a model for the study of early human development.
- Naomi Moris
- , Kerim Anlas
- & Alfonso Martinez Arias
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Article |
Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
Single-cell RNA sequencing and spatial transcriptomics reveal that the somitogenesis clock is active in mouse gastruloids, which can be induced to generate somites with the correct rostral–caudal patterning.
- Susanne C. van den Brink
- , Anna Alemany
- & Alexander van Oudenaarden
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Article |
SPEN integrates transcriptional and epigenetic control of X-inactivation
The transcriptional repressor SPEN bridges the non-coding RNA Xist to transcription machinery, histone deacetylases and chromatin remodelling factors to initiate X-chromosome inactivation.
- François Dossin
- , Inês Pinheiro
- & Edith Heard
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Article |
Dynamic lineage priming is driven via direct enhancer regulation by ERK
ERK reversibly regulates embryonic stem cell transcription via selective redistribution of co-factors and RNA polymerase from pluripotency to early differentiation enhancers, while leaving transcription factors bound to their enhancers, thus preserving plasticity.
- William B. Hamilton
- , Yaron Mosesson
- & Joshua M. Brickman
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Matters Arising |
Reversion after replacement of mitochondrial DNA
- Gavin Hudson
- , Yuko Takeda
- & Mary Herbert
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Matters Arising |
Reply to: Reversion after replacement of mitochondrial DNA
- Eunju Kang
- , Amy Koski
- & Shoukhrat Mitalipov
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Letter |
Controlled modelling of human epiblast and amnion development using stem cells
Landmarks of early stages of human embryogenesis can be recapitulated in a highly controllable and scalable fashion by culturing human pluripotent stem cells in a microfluidic device.
- Yi Zheng
- , Xufeng Xue
- & Jianping Fu
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Letter |
Molecular architecture of lineage allocation and tissue organization in early mouse embryo
Spatially resolved transcriptomes of cell populations at defined positions in the early mouse embryo reveal molecular bases of lineage specification and tissue patterning.
- Guangdun Peng
- , Shengbao Suo
- & Naihe Jing
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Article |
Charting cellular identity during human in vitro β-cell differentiation
Single-cell transcriptional profiling of in vitro human pancreatic β-cell differentiation reveals progenitor and terminal fates, produces a detailed time course of endocrine induction and underpins a lineage model.
- Adrian Veres
- , Aubrey L. Faust
- & Douglas A. Melton
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Letter |
Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids
Cultures grown from small aggregates of mouse embryonic stem cells can be induced to organize spatial and temporal patterns of gene expression that parallel those of the early embryo, offering a potentially useful system for studying early development.
- Leonardo Beccari
- , Naomi Moris
- & Alfonso Martinez Arias
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Letter |
OTX2 restricts entry to the mouse germline
The transcription factor OTX2 ensures that germline induction is initially kept in check and only proceeds after OTX2 downregulation.
- Jingchao Zhang
- , Man Zhang
- & Ian Chambers
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Letter |
Self-organization of a human organizer by combined Wnt and Nodal signalling
Stimulation of Wnt and Nodal pathways in micropatterned human embryonic stem cell colonies induce these colonies to exhibit characteristic spatial expression patterns of the organizer and reproduce organizer function when grafted into a host embryo.
- I. Martyn
- , T. Y. Kanno
- & A. H. Brivanlou
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Letter |
Blastocyst-like structures generated solely from stem cells
Trophoblast and embryonic stem cells interact in vitro to form structures that resemble early blastocysts, and the embryo provides signals that drive early trophectoderm development and implantation.
- Nicolas C. Rivron
- , Javier Frias-Aldeguer
- & Niels Geijsen
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Letter |
The SMAD2/3 interactome reveals that TGFβ controls m6A mRNA methylation in pluripotency
The SMAD2 and SMAD3 protein interactome links TGFβ signalling to diverse effectors including m6A methyltransferase, which has a role in regulating differentiation of human pluripotent stem cells.
- Alessandro Bertero
- , Stephanie Brown
- & Ludovic Vallier
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Letter |
Pluripotent state transitions coordinate morphogenesis in mouse and human embryos
Exit of epiblasts from an unrestricted naive pluripotent state is required for epithelialization and generation of the pro-amniotic cavity in mouse embryos and for amniotic cavity formation in human embryos and human embryonic stem cells.
- Marta N. Shahbazi
- , Antonio Scialdone
- & Magdalena Zernicka-Goetz
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Letter |
Establishment of mouse expanded potential stem cells
Cultures of expanded potential stem cells can be established from individual eight-cell blastomeres, and by direct conversion of mouse embryonic stem cells and induced pluripotent stem cells, highlighting the feasibility of establishing expanded potential stem cells for other mammalian species.
- Jian Yang
- , David J. Ryan
- & Pentao Liu
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Article |
Genome editing reveals a role for OCT4 in human embryogenesis
Genome editing in human zygotes shows that OCT4 is required for normal development at an earlier stage in humans than in mice.
- Norah M. E. Fogarty
- , Afshan McCarthy
- & Kathy K. Niakan
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Letter |
Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells
Long-term culture of male embryonic stem cells in naive conditions containing Mek1/2 and Gsk3a/b inhibitors leads to irreversible changes in epigenetic and genomic stability that compromise their in vivo developmental potential.
- Jiho Choi
- , Aaron J. Huebner
- & Konrad Hochedlinger
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Letter |
Derivation of ground-state female ES cells maintaining gamete-derived DNA methylation
Derivation of female mouse embryonic stem cells under certain conditions induces a loss of DNA methylation and erasure of genomic imprints, which are not recovered and that may contribute to observed impaired development.
- Masaki Yagi
- , Satoshi Kishigami
- & Yasuhiro Yamada
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Letter |
Principles of early human development and germ cell program from conserved model systems
The authors trace the emergence of porcine primordial germ cells and develop in vitro models of primordial germ cell development from human and monkey pluripotent stem cells in order to provide insight into early human development.
- Toshihiro Kobayashi
- , Haixin Zhang
- & M. Azim Surani
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Letter |
Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations
The authors surveyed whole-exome and RNA-sequencing data from 252 unique pluripotent stem cell lines, some of which are in the pipeline for clinical use, and found that approximately 5% of cell lines had acquired mutations in the TP53 gene that allow mutant cells to rapidly outcompete non-mutant cells, but do not prevent differentiation.
- Florian T. Merkle
- , Sulagna Ghosh
- & Kevin Eggan
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Article |
Complex multi-enhancer contacts captured by genome architecture mapping
A technique called genome architecture mapping (GAM) involves sequencing DNA from a large number of thin nuclear cryosections to develop a map of genome organization without the limitations of existing 3C-based methods.
- Robert A. Beagrie
- , Antonio Scialdone
- & Ana Pombo
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Article |
Wnt/β-catenin promotes gastric fundus specification in mice and humans
Wnt signalling is shown to be required for specification of the gastric fundus in mice, and was used to develop human gastric organoids with functional fundic cell types.
- Kyle W. McCracken
- , Eitaro Aihara
- & James M. Wells
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Letter |
Inhibition of mTOR induces a paused pluripotent state
Inhibition of mechanistic target of rapamycin (mTOR) suspends mouse blastocyst development and the cells remain ‘paused’ in a reversible pluripotent state, allowing prolonged culture.
- Aydan Bulut-Karslioglu
- , Steffen Biechele
- & Miguel Ramalho-Santos
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Letter |
Reconstitution in vitro of the entire cycle of the mouse female germ line
Using a protocol that recapitulates both meiosis and oocyte growth in vitro, the authors induce mouse pluripotent stem cells to differentiate into fully functional oocytes that can be fertilized and generate viable offspring, thereby recapitulating the full mammalian female germline cycle in a dish.
- Orie Hikabe
- , Nobuhiko Hamazaki
- & Katsuhiko Hayashi
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Article |
DNA methylation on N6-adenine in mammalian embryonic stem cells
The prevalence of N6-adenine DNA methylation in mammals was previously unknown; this study reveals that N6-methyladenine can be found in mouse embryonic stem cells, especially at subfamilies of young (<1.5 million years old) LINE-1 transposons.
- Tao P. Wu
- , Tao Wang
- & Andrew Z. Xiao
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Letter |
Derivation and differentiation of haploid human embryonic stem cells
Haploid human embryonic stem cells have been derived from haploid oocytes, the cells maintain a normal haploid karyotype as pluripotent cells and, unexpectedly, as differentiated cells — loss-of-function genetic screens previously performed with haploid embryonic stem cells in mice can now be performed in humans.
- Ido Sagi
- , Gloryn Chia
- & Nissim Benvenisty
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Letter |
Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease
A differentiation protocol to obtain enteric nervous system (ENS) progenitors and a range of neurons from human pluripotent stem cells is developed; the cells can migrate and graft to the colon of a chick embryo and an adult mouse colon, including in a mouse model of Hirschsprung disease, in which a functional rescue is observed.
- Faranak Fattahi
- , Julius A Steinbeck
- & Lorenz Studer
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Review Article |
Hallmarks of pluripotency
In response to the need for a defined set of criteria to assess stem-cell potency, this review proposes guidelines for the evaluation of newly derived pluripotent stem cells, from functional assays to integrative molecular analyses of transcriptional, epigenetic and metabolic states.
- Alejandro De Los Angeles
- , Francesco Ferrari
- & George Q. Daley
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Letter |
Cell-fate determination by ubiquitin-dependent regulation of translation
This study shows that a vertebrate-specific ubiquitin ligase modulates neural crest specification in Xenopus development and human embryonic stem-cell differentiation; a proteomics approach reveals that the CUL3KBTBD8 ligase modulates translation by targeting the modulators of ribosomes production NOLC1 and its paralogue TCOF1, which is mutated in a neural-crest-associated syndrome.
- Achim Werner
- , Shintaro Iwasaki
- & Michael Rape
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Letter |
Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells
The human endogenous retrovirus HERVK is normally silenced, but here the surprising discovery is made that in early human embryo development it is expressed, producing retroviral-like particles.
- Edward J. Grow
- , Ryan A. Flynn
- & Joanna Wysocka
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Article
| Open AccessChromatin architecture reorganization during stem cell differentiation
An analysis of genome-wide chromatin interactions during human embryonic stem cell differentiation reveals changes in chromatic organization and simultaneously identifies allele-resolved chromatin structure and differences in gene expression during differentiation.
- Jesse R. Dixon
- , Inkyung Jung
- & Bing Ren
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Article |
Deconstructing transcriptional heterogeneity in pluripotent stem cells
This study uses single-cell expression profiling of pluripotent stem cells after various perturbations, and uncovers a high degree of variability that can be inherited through cell divisions—modulating microRNA or external signalling pathways induces a ground state with reduced gene expression heterogeneity and a distinct chromatin profile.
- Roshan M. Kumar
- , Patrick Cahan
- & James J. Collins
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Letter |
Modelling human development and disease in pluripotent stem-cell-derived gastric organoids
The in vitro generation, from pluripotent stem cells, of three-dimensional human gastric organoids (hGOs) that contain a physiological gastric epithelium comprising both progenitor and differentiated cell types, and have expected functional characteristics is described, as is modelling the pathophysiological response of the human stomach to Helicobacter pylori using these hGOs.
- Kyle W. McCracken
- , Emily M. Catá
- & James M. Wells
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Letter |
Mechanism of Dis3l2 substrate recognition in the Lin28–let-7 pathway
The structure of mouse Dis3l2 bound to an oligoU substrate shows a funnel-like substrate-binding site with the RNA being fed into the active site along a path that is distinct from that seen in the related catalytic subunit of the exosome — 12 uracils of the oligoU-tailed RNA are recognized in a complex network of interactions, suggesting the basis for target specificity.
- Christopher R. Faehnle
- , Jack Walleshauser
- & Leemor Joshua-Tor
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Letter |
RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast
The ubiquitin ligase RLIM is known to activate the long non-coding RNA Xist, which is crucial for X-chromosome inactivation in female mice; however, unlike imprinted X-chromosome inactivation that requires RLIM for Xist expression, evidence is now provided that during random X-chromosome inactivation Xist expression is regulated by an RLIM-independent pathway in vivo.
- JongDae Shin
- , Mary C. Wallingford
- & Ingolf Bach