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| Open AccessTransit amplifying cells coordinate mouse incisor mesenchymal stem cell activation
Mouse incisor growth depends upon mesenchymal stromal cells (MSCs) and transit amplifying cells (TACs). Here the authors describe a distinct population of MSCs that is maintained by TACs through Dlk1 ligand and that contribute to MTACs and mesenchymal lineages including dental pulp and odontoblasts.
- Jemma Victoria Walker
- , Heng Zhuang
- & Bing Hu
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Article
| Open AccessDevelopmental kinetics and transcriptome dynamics of stem cell specification in the spermatogenic lineage
In neonatal testes, prospermatogonia generate both spermatogonia for the first wave of spermatogenesis and spermatogonial stem cells (SSCs) for maintenance of spermatogenesis in males. Here the authors characterize the development of mouse SSCs from prospermatogonia using single-cell RNA-seq and transplantation assays.
- Nathan C. Law
- , Melissa J. Oatley
- & Jon M. Oatley
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Article
| Open AccessA comprehensive single cell transcriptional landscape of human hematopoietic progenitors
Human Hematopoietic stem and progenitor cells (HSPCs) are commonly defined by CD34 expression. Here, the authors map single-cell RNA states both inside and outside the CD34 compartment, uncovering previously unappreciated branchpoints and validating CD164 as an efficient marker for early HSPCs.
- Danilo Pellin
- , Mariana Loperfido
- & Luca Biasco
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Article
| Open AccessPax3 cooperates with Ldb1 to direct local chromosome architecture during myogenic lineage specification
Chromatin looping allows for enhancer–promoter interactions that regulate transcription. Here the authors show that activation of embryonic myogenesis is associated with establishment of long-range chromatin interactions centred on Pax3-bound loci and find that Ldb1 functions as the mediator of looping interactions at a subset of Pax3 binding sites.
- Alessandro Magli
- , June Baik
- & Rita C. R. Perlingeiro
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Article
| Open AccessFunctional cardiac fibroblasts derived from human pluripotent stem cells via second heart field progenitors
Cardiac fibroblasts (CFs) play critical roles in heart development, homeostasis, and disease. Here the authors efficiently differentiate human pluripotent stem cells through second heart field progenitors to CFs that exhibit features and functional properties similar to native CFs.
- Jianhua Zhang
- , Ran Tao
- & Timothy J. Kamp
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Article
| Open AccessSALL3 expression balance underlies lineage biases in human induced pluripotent stem cell differentiation
Human induced pluripotent stem cells (hiPSCs) generate all cell types in the body, but different lines can differ in their potential. Here, the authors determine that higher endogenous levels of SALL3 in hiPSCs lead to ectoderm differentiation bias and reduced mesoderm/endoderm due to DNMT3B mediated DNA methylation.
- Takuya Kuroda
- , Satoshi Yasuda
- & Yoji Sato
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Article
| Open AccessDynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory
The spatial organization of the genome plays an important but unclearly defined role in gene regulation. Here, the authors integrate Hi-C, RNA-seq and ATAC-seq data to map cardiogenesis from pluripotent stem cells and describe an RBM20-dependent splicing factory assembling the TTN locus with other RBM20 targets.
- Alessandro Bertero
- , Paul A. Fields
- & Charles E. Murry
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Article
| Open AccessYAP inhibition enhances the differentiation of functional stem cell-derived insulin-producing β cells
Pluripotent stem cells can be directed into insulin-producing beta cells in vitro. Here, the authors show that downregulation of YAP, an effector of the Hippo pathway, enhances endocrine progenitor differentiation and the generation of beta-cells with improved insulin secretion.
- Edwin A. Rosado-Olivieri
- , Kendall Anderson
- & Douglas A. Melton
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Article
| Open AccessGenetic programming of macrophages generates an in vitro model for the human erythroid island niche
In vitro differentiation of red blood cells (RBCs) is a desirable therapy for various disorders. Here the authors develop a culture system using stem cell-derived macrophages to show that inducible expression of a transcription factor, KLF1, enhances RBC production, potentially through the induction of three soluble factors, ANGPTL7, IL33 and SERPINB2.
- Martha Lopez-Yrigoyen
- , Cheng-Tao Yang
- & Lesley M. Forrester
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Article
| Open AccessAnti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells
Enhanced Wnt receptor activity is a major cause of cancer development. Here the authors identify camelid single-domain antibody fragments (VHHs) that bind to the Wnt receptor LRP5/6 ectodomain, determine the crystal structures and show that these VHHs selectively inhibit Wnt3- mediated cellular responses and block the growth of mutant Wnt-hypersensitive intestinal tumor organoids.
- Nicola Fenderico
- , Revina C. van Scherpenzeel
- & Madelon M. Maurice
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Article
| Open Access3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening
Studies examining human podocytopathies have utilised 2D cultured primary or immortalised podocyte cell lines. Here, the authors demonstrate that 3D human glomeruli sieved from induced pluripotent stem cell-derived kidney organoids retain an improved podocyte identity in vitro facilitating disease modelling and toxicity testing.
- Lorna J. Hale
- , Sara E. Howden
- & Melissa H. Little
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Article
| Open AccessNuRD-interacting protein ZFP296 regulates genome-wide NuRD localization and differentiation of mouse embryonic stem cells
The NuRD complex plays an important role in regulating lineage commitment and cell fate during early embryonic development. Here the authors present an integrative analysis of MBD3/NuRD composition and binding in mouse embryonic stem cells and neural progenitor cells, providing a molecular basis for genome-wide NuRD localization
- Susan L. Kloet
- , Ino D. Karemaker
- & Michiel Vermeulen
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Article
| Open AccessDynamic intercellular transport modulates the spatial patterning of differentiation during early neural commitment
How heterogeneities arise in stem cell populations remains unclear. Here, Glen et al. find that in ESC colonies cell cycle asynchronies modulate gap junctions, causing variation in intracellular signalling molecule diffusion between cells, and ultimately in spatial heterogeneity in differentiation.
- Chad M. Glen
- , Todd C. McDevitt
- & Melissa L. Kemp
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Article
| Open AccessBi-directional cell-pericellular matrix interactions direct stem cell fate
3D hydrogels have provided information on the physical requirements of stem cell fate, but the contribution of interactions with the pericellular environment are under-explored. Here the authors show that pericellular matrix secreted by human bone marrow stromal cells (hMSC) embedded in a HA-based hydrogel contribute to hMSC fate.
- Silvia A. Ferreira
- , Meghna S. Motwani
- & Eileen Gentleman
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Article
| Open AccessMed23 serves as a gatekeeper of the myeloid potential of hematopoietic stem cells
Hematopoietic stem cells (HSCs) in the bone marrow are quiescent, but are activated in response to stress. Here, the authors show that loss of Med23 leads to greater activation and enhanced myeloid potential of HSCs in response to stress, also Med23 maintains stemness gene expression and suppresses myeloid genes.
- Xufeng Chen
- , Jingyao Zhao
- & Xiaolong Liu
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Article
| Open AccessInterleukin-2 induces the in vitro maturation of human pluripotent stem cell-derived intestinal organoids
Human pluripotent stem cell-derived intestinal organoids (hIOs) are a useful model with which to study intestinal development and disease, but they require in vivo maturation to resemble adult tissue. Here, the authors show that T lymphocyte-derived IL-2 induces hIO maturation in vitro through the activation of STAT3.
- Kwang Bo Jung
- , Hana Lee
- & Mi-Young Son
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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 AccessFGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells
Merkel cells are mechanoreceptors located in the epidermis whose developmental origin is unclear. Here the authors show that Merkel cells originate from SOX9 positive cells inside hair follicles and that FGFR2-mediated epithelial signalling is required for their specification.
- Minh Binh Nguyen
- , Idan Cohen
- & Elena Ezhkova
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Article
| Open AccessHematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice
Dependence of hematopoietic stem cell (HSC) fate on the phase of the cell cycle has not been demonstrated in vivo. Here, the authors find that HSCs can differentiate into a downstream progenitor without physical division, even before progressing into the S phase of the cell cycle.
- Tatyana Grinenko
- , Anne Eugster
- & Ben Wielockx
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Article
| 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 AccessReconstruction of complex single-cell trajectories using CellRouter
Single cell analysis provides insight into cell states and transitions, but to interpret the data, improved algorithms are needed. Here, the authors present CellRouter as a method to analyse single-cell trajectories from RNA-sequencing data, and provide insight into erythroid, myeloid and lymphoid differentiation.
- Edroaldo Lummertz da Rocha
- , R. Grant Rowe
- & George Q. Daley
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Article
| Open AccessCardiogenic programming of human pluripotent stem cells by dose-controlled activation of EOMES
The T-box transcription factor eomesodermin (EOMES) acts both in endoderm specification as well as heart development, suggesting context-specific function. Here, the authors show that dose-controlled EOMES induction is sufficient for cardiogenic programming of human pluripotent stem cells.
- Martin J. Pfeiffer
- , Roberto Quaranta
- & Boris Greber
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Article
| Open AccessMechanically-sensitive miRNAs bias human mesenchymal stem cell fate via mTOR signalling
Mesenchymal stem cell (MSC) fate can be mechanically regulated by substrate stiffness but this is difficult to control in a 3D hydrogel. Here the authors identify miRNAs that change expression in response to substrate stiffness and RhoA signalling and show that they can bias MSC fate in a 3D soft hydrogel.
- Jessica E. Frith
- , Gina D. Kusuma
- & Justin J. Cooper-White
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Article
| Open AccessEngineering human pluripotent stem cells into a functional skeletal muscle tissue
The generation of functional skeletal muscle tissue from human pluripotent stem cells has not been reported. Here, the authors describe engineering of contractile skeletal muscle bundles in culture, which become vascularized and maintain functionality when transplanted into mice.
- Lingjun Rao
- , Ying Qian
- & Nenad Bursac
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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 AccessCardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues
Cardiomyocytes derived from human induced pluripotent stem cells could be used to generate cardiac tissues for regenerative purposes. Here the authors describe a method to obtain large bioengineered heart tissues showing advanced maturation, functional features and engraftment capacity.
- Ilya Y. Shadrin
- , Brian W. Allen
- & Nenad Bursac
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Article
| Open AccessMicroRNAs promote skeletal muscle differentiation of mesodermal iPSC-derived progenitors
Mesodermal iPSC-derived progenitors (MiPs) can regenerate both skeletal and cardiac muscle. Here, the authors show that a microRNA cocktail stimulates skeletal muscle differentiation and that human MiPs can engraft into striated muscle in mice.
- Giorgia Giacomazzi
- , Bryan Holvoet
- & Maurilio Sampaolesi
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| 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 AccessGlycoprotein 2 is a specific cell surface marker of human pancreatic progenitors
Pancreatic progenitors (PPs) can be derived from human pluripotent stem cells in vitro but efficiency of differentiation varies, making it hard to sort for insulin-producing cells. Here, the authors use a proteomic approach to identify the secretory granule membrane glycoprotein 2 as a marker for PDX1+/NKX6-1+ PPs.
- Kathryn F. Cogger
- , Ankit Sinha
- & M. Cristina Nostro
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Article
| Open AccessROCKII inhibition promotes the maturation of human pancreatic beta-like cells
Our incomplete understanding of how pancreatic beta cells form limits the generation of beta-like cells from human pluripotent stem cells (hPSC). Here, the authors identify a ROCKII inhibitor H1152 as increasing insulin secreting cells from hPSCs and improving beta-cell maturation on transplantation in vivo.
- Zaniar Ghazizadeh
- , Der-I Kao
- & Shuibing Chen
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Article
| Open AccessIn vitro differentiation of human embryonic stem cells into ovarian follicle-like cells
In vitro production of human oocytes for the treatment of female infertility is a goal in reproductive medicine. Here, the authors establish in vitroconditions to generate human ovarian follicle-like cells from human embryonic stem cells.
- Dajung Jung
- , Jie Xiong
- & Kehkooi Kee
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Article
| Open AccessEngineering the haemogenic niche mitigates endogenous inhibitory signals and controls pluripotent stem cell-derived blood emergence
The derivation of blood progenitor cells from human pluripotent stem cells is of interest for cell therapy but remains an inefficient process. Here the authors micropattern hPSC-derived haemogenic endothelial (HE) cells into spatially-organized, size-controlled colonies and identify a geometry that achieves increased efficiency in deriving blood cells.
- Nafees Rahman
- , Patrick M. Brauer
- & Peter W. Zandstra
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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 Accessp190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation
The success of hematopoietic stem cell (HSC) transplantation relies on understanding what regulates the fate decision to self-renew. Here, the authors show using bothin vitro assays and in vivotransplantation that loss of the RhoGAP p190-B enhances self-renewal by inhibiting TGFβ/p38 signalling.
- Ashwini Hinge
- , Juying Xu
- & Marie-Dominique Filippi
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Article
| Open AccessDNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation
DNMT3A mutations are known to cause acute myeloid leukaemia. Here, Koya et al. show that DNMT3A R882H mutation causes monoblastic transformation and haematopoietic stem cell accumulation in a methylation-independent manner, by suppressing the polycomb repressive complex 1, causing transcriptional silencing.
- Junji Koya
- , Keisuke Kataoka
- & Mineo Kurokawa
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Article
| Open AccessAccumulation of differentiating intestinal stem cell progenies drives tumorigenesis
Intestinal homeostasis is ensured by stem cell self-renewal and differentiation while alterations of these processes can lead to cancer. In this study, using Drosophilagenetics the authors demonstrate that the loss of the transcription factor Sox21a blocks the differentiation of the intestinal stem cell progeny, which accumulate and form aggressive tumours.
- Zongzhao Zhai
- , Shu Kondo
- & Bruno Lemaitre
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Article
| Open AccessPrmt5 is a regulator of muscle stem cell expansion in adult mice
Skeletal muscle satellite cells are important for muscle regeneration, but their regulatory mechanisms are largely unknown. Here the authors identify arginine methyltransferase Prmt5 as a key regulator of satellite cell maintenance and function in adult mice, and show that Prmt5 acts mainly but not exclusively on the cell cycle inhibitor p21.
- Ting Zhang
- , Stefan Günther
- & Thomas Braun
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Article
| Open AccessPI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation
Although crosstalk between the phosphatidylinositol 3-kinase (PI3K) and transforming growth factor-β pathways is important, the mechanism is obscure. Here, Yu et al. show that activation of mTORC2 downstream of PI3K leads to the linker phosphorylation of Smad2/3 and their ubiquitin-dependent degradation.
- Jason S. L. Yu
- , Thamil Selvee Ramasamy
- & Wei Cui
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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
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Article
| Open AccessTransformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2
The adult gastro-intestinal tract harbours stem cells that differ in their differentiation programme and in the gene repertoire that they express. Here the authors show that single adult Lgr5-positive stem cells require Cdx2 to maintain their intestinal identity and are converted into pyloric stem cells in the absence of this transcription factor.
- Salvatore Simmini
- , Monika Bialecka
- & Jacqueline Deschamps
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Article |
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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Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in embryonic stem cells
The Krüppel-like factors Klf4 and Klf5 have wide roles in cell biology including the regulation of pluripotency. In this study, Aksoy et al. demonstrate that Klf4 preferentially blocks the expression of endodermal markers in embryonic stem cells, whereas Klf5 negatively regulates mesodermal factors.
- Irène Aksoy
- , Vincent Giudice
- & Pierre Savatier
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Article |
Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells
The histone demethylase Lsd1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Here, the authors show that the loss of Lsd1 in the trophectoderm of mouse embryos leads to premature differentiation of trophoblast stem cells, partially due to de-repression of the transcription factor Ovol2.
- Dongmei Zhu
- , Stefanie Hölz
- & Roland Schüle
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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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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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Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation
Chromatin in embryonic stem cells is present in an open state presumably to facilitate gene expression changes required for pluripotency and subsequent multilineage differentiation. This study describes roles for lamin A, histone acetylation and G9a-mediated histone H3 lysine 9 methylation in regulating chromatin plasticity in these cells.
- Shai Melcer
- , Hadas Hezroni
- & Eran Meshorer
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Differentiation of multipotent vascular stem cells contributes to vascular diseases
De-differentiation and proliferation of vascular smooth muscle cells is thought to have a dominant role in vascular remodelling. Here, Tanget al. identify a new type of multipotent vascular stem cell in the blood vessel wall that contributes to this process, thereby challenging the established hypothesis.
- Zhenyu Tang
- , Aijun Wang
- & Song Li
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Article
| Open AccessActivin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors
Signalling inputs to neural progenitors regulate the differentiation of the stem cell pool. By analysing the mechanisms occuring during neurogenesis, Cambrayet al. report that activin is the pivotal factor regulating the differentiation of telencephalic neural precursors towards a cortical interneuron fate.
- Serafí Cambray
- , Charles Arber
- & Tristan A. Rodríguez
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Article
| Open AccessIntestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors
Notch inhibitors result in the differentiation of intestinal crypt progenitors into goblet cells, suggesting that they could be of use in treating intestinal neoplasia. Here van Eset al. show that Math1 is required for intestinal cell differentiation induced by Notch inhibition.
- Johan H. van Es
- , Natalie de Geest
- & Bassem A. Hassan