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| Open AccessEmbryos and embryonic stem cells from the white rhinoceros
The Southern (SWR) and Northern (NWR) are two subspecies of the White Rhinoceros with the NWR being almost extinct. Here, using assisted reproduction technology, the authors produce and cryopreserve SWR purebred and NWR-SWR hybrid embryos developed to the blastocyst stage, and also generate embryonic stem cell lines, in an attempt to save genes of the NWR.
- Thomas B. Hildebrandt
- , Robert Hermes
- & Cesare Galli
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Article
| Open AccessUhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a
Uhrf1 is a known regulator of heterochromatin and DNA methylation in embryonic stem cells (ESCs). Here, the authors demonstrate that Uhrf1 acts together with the Set1/COMPASS complex regulator of active transcription to promote H3K4 methylation at bivalent loci and Uhrf1 loss results in disruption of differentiation.
- Kun-Yong Kim
- , Yoshiaki Tanaka
- & In-Hyun Park
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Article
| Open AccessPCGF5 is required for neural differentiation of embryonic stem cells
Polycomb-group proteins are key regulators of transcriptional programs that maintain cell identity. Here the authors provide evidence that PCGF5, a subunit of Polycomb Repressor Complex 1, is important for the differentiation of mouse embryonic stem cells towards a neural cell fate.
- Mingze Yao
- , Xueke Zhou
- & Hongjie Yao
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Article
| Open AccessNOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells
It is unclear whether arterial specification is required for hematopoietic stem cell formation. Here, the authors use a chemically defined human pluripotent stem cell (hPSC) differentiation system to show the role of NOTCH signaling in forming arterial-type hemogenic endothelial cells.
- Gene I. Uenishi
- , Ho Sun Jung
- & Igor I. Slukvin
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Article
| Open AccessP53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development
During embryo development, cell fitness determines survival but how this is regulated is unclear. Here, the authors show that in early embryonic development and stem cells exiting the naive state, cells sense the fitness of their neighbours and trigger p53 to repress mTOR to eliminate a third of cells.
- Sarah Bowling
- , Aida Di Gregorio
- & Tristan A. Rodríguez
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| Open AccessZeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells
The production of nitric oxide (NO) is required for early stage embryo implantation into the uterus. Here the authors show that during differentiation of naive mouse ESCs, early production of endogenous NO leads to a mesendoderm differentiation commitment pathway by inhibiting the action of the transcriptional repressor Zeb1.
- Chiara Cencioni
- , Francesco Spallotta
- & Carlo Gaetano
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Article
| Open AccessRASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73
In development, the switch from pluripotency to differentiation is important but it is often unclear how it is regulated. Here, the authors show that the tumour suppressor RASSF1A mediates this switch by promoting YAP-p73 transcription, which in turn enables differentiation.
- Angelos Papaspyropoulos
- , Leanne Bradley
- & Eric O’Neill
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Article
| Open AccessParallel derivation of isogenic human primed and naive induced pluripotent stem cells
Derivation of human induced pluripotent stem cells (hiPSCs) produces primed hiPSCs that can in turn be converted to naive hiPSCs. Here, the authors directly reprogram somatic cells to form both naive and primed isogenic hiPSCs and confirm the similarity of naive hiPSCs to their in vivo counterparts.
- Stéphanie Kilens
- , Dimitri Meistermann
- & Matthew L. Albert
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Article
| Open AccessSilencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency
The efficiency of somatic cell reprogramming is lowered by ageing. Here the authors show that the transcription factor Zeb2 and its long non-coding RNA Zeb2-NAT are expressed at high levels in older fibroblasts and their inhibition increases reprogramming efficiency.
- Bruno Bernardes de Jesus
- , Sérgio Pires Marinho
- & Maria Carmo-Fonseca
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Article
| Open AccessInference of differentiation time for single cell transcriptomes using cell population reference data
Single cell transcriptome data can be used to determine developmental lineage trajectories. Here the authors map single cell transcriptomes onto a differentiation trajectory defined by cell population transcriptomes and show that cell cycle regulators have a role in differentiation timing.
- Na Sun
- , Xiaoming Yu
- & Jing-Dong J. Han
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Article
| Open AccessA transcribed enhancer dictates mesendoderm specification in pluripotency
Long noncoding RNAs (lncRNAs) are key regulators of lineage specification during development. Here, the authors investigate remodeling of enhancers and regulation of the lncRNA transcriptome during mesendoderm specification, and identify a pluripotent stage-specific transcribed enhancer controlling adoption of the mesendodermal cell fate.
- Michael Alexanian
- , Daniel Maric
- & Thierry Pedrazzini
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Article
| Open AccessA post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells
Unlike transcriptional regulation of hESC identity, little is known post-transcriptionally. Here, the authors show that the RNA binding protein CSDE1 regulates core components of hESC identity, neurectoderm commitment and neurogenesis to maintain pluripotency and prevent neural differentiation.
- Hyun Ju Lee
- , Deniz Bartsch
- & David Vilchez
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Article
| Open AccessThe Polycomb group protein CBX6 is an essential regulator of embryonic stem cell identity
In mammals, five different CBX proteins can be part of Polycomb repressive complex 1 (PRC1). Here, the authors provide evidence that CBX6 plays an essential role in regulating pluripotency in embryonic stem cells and that CBX6 functions as part of both canonical and non-canonical PRC1 complexes.
- Alexandra Santanach
- , Enrique Blanco
- & Luciano Di Croce
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Article
| Open AccessStructural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX
The ATRX-DAXX histone chaperone complex incorporates H3.3 in heterochromatin in a replication-independent manner. Here, the authors present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX, and characterize ATRX-dependent and-independent functions of DAXX.
- Dominik Hoelper
- , Hongda Huang
- & Peter W. Lewis
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Article
| Open AccessThe circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency
Circular RNAs are abundant in the transcriptome and are implicated in the regulation of a range of biological processes. Here the authors identify circBIRC6 as a microRNA sponge that helps modulate human pluripotency and early lineage differentiation.
- Chun-Ying Yu
- , Tung-Cheng Li
- & Hung-Chih Kuo
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Article
| Open AccessDynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells
Commitment to different fates by differentiating pluripotent cells depends upon integration of external and internal signals. Here the authors analyse the entry of mouse embryonic stem cells into retinoic acid-mediated differentiation using single cell transcriptomics with high temporal resolution.
- Stefan Semrau
- , Johanna E. Goldmann
- & Alexander van Oudenaarden
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Article
| Open AccessOCT4 impedes cell fate redirection by the melanocyte lineage master regulator MITF in mouse ESCs
Lineage master regulators induce differentiation and how the melanocyte master regulator Microphthalmia-associated transcription factor (MITF) is regulated is unclear. Here, the authors show that the pluripotency master regulator, OCT4, counteracts differentiation induced by MITF in mouse embryonic stem cells.
- Danna Sheinboim
- , Itay Maza
- & Carmit Levy
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Article
| Open AccessThe WNT target SP5 negatively regulates WNT transcriptional programs in human pluripotent stem cells
WNT/β-catenin signaling is an essential regulator of many developmental processes. Here, the authors provide evidence that activation of the WNT in human pluripotent stem cells leads to expression WNT target gene SP5, which then acts to diminish expression of active WNT target genes.
- Ian J. Huggins
- , Tomas Bos
- & Karl Willert
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Article
| Open AccessPRC2 specifies ectoderm lineages and maintains pluripotency in primed but not naïve ESCs
Polycomb repressive complex 2 (PRC2) plays an essential role in development by modifying chromatin but what this means at a cellular level is unclear. Here, the authors show that ablation of PRC2 genes in human embryonic stem cells and in mice results in changes in pluripotency and the primed state of cells.
- Yongli Shan
- , Zechuan Liang
- & Guangjin Pan
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Article
| Open AccessHuman stem cells alter the invasive properties of somatic cells via paracrine activation of mTORC1
Cell invasion is required for several physiological processes but it is unknown if stem cells induce invasiveness in other cells. Here, the authors show that human stem cells secrete insulin-like growth factor, which in turn activates the mTORC1 pathway, initiating invasive behaviour and attracting other cells.
- Margit Rosner
- , Ha Thi Thanh Pham
- & Markus Hengstschläger
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Article
| Open AccessA CRISPR screen identifies genes controlling Etv2 threshold expression in murine hemangiogenic fate commitment
How haematopoietic and endothelial cell lineages are specified is unclear. Here, the authors identify the forkhead transcription factor Foxh1 as regulating FLK1+ mesoderm formation in mouse embryonic stem cells, which in turn specifies hemangiogenic fate via Etv2.
- Haiyong Zhao
- & Kyunghee Choi
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Article
| Open AccessFlipping between Polycomb repressed and active transcriptional states introduces noise in gene expression
Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.
- Gozde Kar
- , Jong Kyoung Kim
- & Sarah A. Teichmann
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Article
| Open AccessCcl2/Ccr2 signalling recruits a distinct fetal microchimeric population that rescues delayed maternal wound healing
Foetal microchimeric cells (FMCs) are found in maternal circulation during pregnancy and migrate to injury sites, where they mediate repair, but how this is regulated is unclear. Here, the authors show in mice that the chemokine Ccl2 enhances delayed maternal wound healing through a subpopulation of Ccr2+ FMCs.
- Mathieu Castela
- , Dany Nassar
- & Selim Aractingi
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Article
| Open AccessA sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes
Reprogramming has been shown to involve EMT-MET; however, its role in cell differentiation is unclear. Here the authors show that duringin vitrodifferentiation of hepatocytes, Activin A-induced formation of definitive endoderm requires EMT mediated by TGFβ signalling, followed by a MET process.
- Qiuhong Li
- , Andrew P. Hutchins
- & Duanqing Pei
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Article
| Open AccessDirect comparison of distinct naive pluripotent states in human embryonic stem cells
Human embryonic stem cells (hESCs) in culture display a state of primed pluripotency, but recent protocols have been developed that enable hESCs to adopt a naive-like pluripotent state. Here the authors perform a side-by-side comparison of methods used to culture naive hESCs and confirm the role of PI3K/AKT/mTORC signalling in facilitating the induction of naive pluripotency.
- S. Warrier
- , M. Van der Jeught
- & B. Heindryckx
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Article
| Open AccessLipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells
There are two technical impediments for using purified Wnt proteins in serum-free stem cell cultures: rapid loss of activity and toxicity of detergents to stem cell self-renewal. Here, the authors show that lipid-stabilized Wnt3a can establish long-term culture of human intestinal and liver organoids.
- Nesrin Tüysüz
- , Louis van Bloois
- & Derk ten Berge
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| Open AccessThe impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells
MicroRNAs can posttranscriptionally repress multiple targets in a cell population. Here the authors use single-cell sequencing to investigate the effects of an individual miRNA on transcriptional heterogeneity and gene co-expression
- Gennaro Gambardella
- , Annamaria Carissimo
- & Robert Blelloch
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| Open AccessBulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells
Differentiation of human pluripotent stem cells (hPSC) mimics aspects of embryonic developmentin vitrobut is poorly understood. Here, the authors identify bulk cell density as a key parameter directing transition from pluripotency to primitive streak-like priming in hPSCs via secreted LEFTY/CERBERUS.
- Henning Kempf
- , Ruth Olmer
- & Robert Zweigerdt
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Article
| Open AccessThe deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog
Nanog regulates embryonic stem cell (ESC) pluripotency but what controls Nanog protein stability is unclear. Here, the authors show that in mouse ESCs, Nanog protein is ubiquitinated and stabilized by the deubiquitinase USP21, which in turn is regulated by extrinsic signals, STAT3 and ERK.
- Jiali Jin
- , Jian Liu
- & Ping Wang
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Article
| Open AccessLong non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling
Long non-coding RNAs (lncRNA) are known to regulate human embryonic stem cell (hESC) self-renewal. Here, the authors identify lncRNA growth-arrest-specific transcript 5 (GAS5) that regulates pluripotency via modulation of NODAL signalling to maintain self-renewal in hESCs.
- Chen Xu
- , Yan Zhang
- & Houqi Liu
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Article
| Open AccessBioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction
Stem cell therapy of myocardial infarction is hampered by poor survival of injected cells. Here the authors develop injectable aggregates of stem cells differentiated to an early cardiac stage and encapsulated in a biodegradable micromatrix, and show their enhanced therapeutic efficacy in a heart infarction mouse model.
- Shuting Zhao
- , Zhaobin Xu
- & Xiaoming He
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Article
| Open AccessCripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency
Stem cell plasticity is crucial for early embryo development and the differentiation of stem cells. Here, the authors show that the extracellular protein Cripto sustains mouse ESC self-renewal and maintains mouse EpiSC as well as human ESC pluripotency and controls the metabolic reprogramming in ESCs to EpiSC transition.
- Alessandro Fiorenzano
- , Emilia Pascale
- & Gabriella Minchiotti
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| Open AccessA Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity
The Myc transcription factor is a major regulator of stem cell (SC) self-renewal and pluripotency but how this integrates signals from other pathways is unclear. Here, the authors show that Myc activation triggers epigenetic memory in self renewing embryonic SCs via PRC2-mediated potentiation of the Wnt pathway.
- Luca Fagnocchi
- , Alessandro Cherubini
- & Alessio Zippo
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Article
| Open AccessMicrovesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation
It is unclear how embryonic stem cells (ESC) communicate with surrounding cells during implantation. Here, the authors show that microvesicles (MV) are shed from ESCs, activating integrin and JNK/FAK kinases in trophoblasts, stimulating migration in vitro, and injecting MVs enhances blastocyst implantation.
- Laura M. Desrochers
- , François Bordeleau
- & Marc A. Antonyak
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Article
| Open AccessGeneration of mice with longer and better preserved telomeres in the absence of genetic manipulations
Telomere shortening has been linked to some aspects of organismal ageing. Here the authors create chimaeric mice that contain a mix of cells with normal or unnaturally long telomeres, and show chimaeric mice are protected from some forms of ageing-associated cellular damage and have accelerated wound-healing.
- Elisa Varela
- , Miguel A. Muñoz-Lorente
- & Maria A. Blasco
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Article
| Open AccessEpigenetic profiles signify cell fate plasticity in unipotent spermatogonial stem and progenitor cells
Spermatogonial stem cells (SSCs) spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here, the authors reveal the dynamics of bivalent histone H3-lysine4 and -lysine27 methylation signatures at somatic gene promoters in SSCs and ESC-like promoter chromatin states in MASCs.
- Ying Liu
- , Eugenia G. Giannopoulou
- & Marco Seandel
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Article
| Open AccessEssential role of the TFIID subunit TAF4 in murine embryogenesis and embryonic stem cell differentiation
The role of TFIID core module TAFs (TATA-binding protein-associated factors) in embryogenesis is unknown. Here, the authors show that Taf4 is essential at mid-gestation and for complete neuronal differentiation of embryonic stem cells, but that Taf4a and Taf4b are redundant at early embryonic stages.
- Diana Langer
- , Igor Martianov
- & Irwin Davidson
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Article
| Open AccessLoss of MAX results in meiotic entry in mouse embryonic and germline stem cells
The mechanisms that trigger meiosis in germ cells and halt this process in non-germline cells are unclear. Here, the authors show that knockout of Maxin embryonic stem cells results in meiotic onset in a mechanism that involves the PRC1 complex.
- Ayumu Suzuki
- , Masataka Hirasaki
- & Akihiko Okuda
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Article
| Open AccessEndothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells
Understanding coronary vessels development provides basis for regenerative strategies. Here, Soh et al. identify endothelin-1 as a key molecule driving long-term expansion of ISL1+bipotent vascular progenitors derived from human embryonic stem cells, and show that these cells can regenerate coronary vessels in mice.
- Boon-Seng Soh
- , Shi-Yan Ng
- & Kenneth R. Chien
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Article
| Open AccessA short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells
In fast proliferating embryonic stem cells (ESC) the DNA damage response is activated by mechanisms that are as yet elusive. Here, Ahuja et al.link the DNA damage response to replication stress in mouse ESCs, caused by a short G1 phase, and propose fork remodelling as maintaining genome stability in embryos.
- Akshay K. Ahuja
- , Karolina Jodkowska
- & Massimo Lopes
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Article
| Open AccessFunctional anterior pituitary generated in self-organizing culture of human embryonic stem cells
It is difficult to generate functional human anterior pituitary tissues in vitro. Here, Ozone et al. generate human anterior pituitary from embryonic stem cells by recapitulating in vivodevelopment, and demonstrate this tissue secretes hormones and rescues hypopituitarism when grafted into mice.
- Chikafumi Ozone
- , Hidetaka Suga
- & Yoshiki Sasai
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Article
| Open AccessReprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells
Genetic and epigenetic abnormalities have been found to result from reprogramming of differentiated cells into human induced pluripotent stem cells (hiPSCs). Here, Klawitter et al.identify endogenous L1, Alu and SVA mobilization during reprogramming, highlighting the risk of insertional mutagens in hiPSCs.
- Sabine Klawitter
- , Nina V. Fuchs
- & Gerald G. Schumann
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Article
| Open AccessGeneration of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue
In vitro differentiation of human pluripotent stem cells (hPSCs) has enabled the generation of neuroectodermal tissues. Here, Sakaguchi et al.use a modified neocortical induction method to generate functional hippocampal granule and pyramidal-like neurons, as well as dorsomedial telencephalic tissues from hPSCs.
- Hideya Sakaguchi
- , Taisuke Kadoshima
- & Yoshiki Sasai
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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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Article
| Open AccessFoxp1-mediated programming of limb-innervating motor neurons from mouse and human embryonic stem cells
The differentiation of spinal motor neurons (MNs) from mouse and human embryonic stem cells provides opportunities to model MN development and disease, but most protocols produce only a subset of the MN subtypes found in vivo. Here the authors show that limb projecting lateral motor column MNs can be efficiently generated though the expression of Foxp1.
- Katrina L. Adams
- , David L. Rousso
- & Bennett G. Novitch
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Article
| Open AccessPontin functions as an essential coactivator for Oct4-dependent lincRNA expression in mouse embryonic stem cells
Long non-coding RNAs or lincRNAs identified in embryonic stem (ES) cells have been shown to regulate ES cell states; however, how these lincRNAs are regulated remains unclear. Here the authors show that the transcriptional coactivator Pontin regulates the expression of lincRNAs involved in ES cell maintenance in an Oct4-dependent manner.
- Kyungjin Boo
- , Jinhyuk Bhin
- & Sung Hee Baek
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HEB associates with PRC2 and SMAD2/3 to regulate developmental fates
In embryonic stem cells, extracellular signals are required to derepress developmental promoters to drive lineage specification, but the proteins involved in this process remain unknown. Here the authors show that the protein HEB directly associates with the Polycomb repressive complex 2 at genes involved in mesoderm and endoderm specification.
- Se-Jin Yoon
- , Joseph W. Foley
- & Julie C. Baker
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Article
| Open AccessActivated astrocytes enhance the dopaminergic differentiation of stem cells and promote brain repair through bFGF
In the adult brain, the neurotrophic factor basic fibroblast growth factor (bFGF) is predominantly secreted by astrocytes. Here the authors use optogenetics to activate astrocytes, leading to release of bFGF, inducing enhanced dopaminergic differentiation of neural progenitors and promoting brain repair in a mouse Parkinson’s disease model.
- Fan Yang
- , Yunhui Liu
- & Liping Wang