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| Open AccessOncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation
Activating mutations of the tyrosine kinase Kit are commonly found in mast cell neoplasms and gastrointestinal stromal tumours. Here the authors show that mutant Kit, through the activation of PI3K and STAT3 pathways, elicits proliferative and survival signals from endolysosomes and from the endoplasmic reticulum.
- Yuuki Obata
- , Shota Toyoshima
- & Ryo Abe
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Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion
Long, thin projections of the cell membrane known as cytonemes are required for signalling by the secreted morphogen Hedgehog. Gradilla et al.show that cytonemes carry Hedgehog-associated exovesicles, and that exovesicle formation is required for graded Hedgehog signalling.
- Ana-Citlali Gradilla
- , Esperanza González
- & Isabel Guerrero
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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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Article
| Open AccessEvolutionary innovation and conservation in the embryonic derivation of the vertebrate skull
It is unclear whether the embryonic origin of skull bones is evolutionarily conserved. Here, the authors show that the pattern of cranial development of the Mexican axolotl is similar to that reported for other vertebrates, but the pattern in the African clawed frog, another amphibian, is unique.
- Nadine Piekarski
- , Joshua B. Gross
- & James Hanken
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FGF signalling restricts haematopoietic stem cell specification via modulation of the BMP pathway
BMP signalling is required for the emergence of haematopoietic stem cells (HSCs) from the zebrafish dorsal aorta. Here the authors show that FGF signalling negatively regulates HSC emergence by downregulating BMP activity in the zebrafish subaortic mesenchyme and upregulating the expression of BMP antagonists in the somite.
- Claire Pouget
- , Tessa Peterkin
- & Roger Patient
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| Open AccessDouble-sieving-defective aminoacyl-tRNA synthetase causes protein mistranslation and affects cellular physiology and development
Accurate loading of amino acids to their cognate tRNA is essential to avoid mistranslation during protein synthesis, which has been linked to human diseases. Here, Lu et al. present a Drosophilamodel that demonstrates the necessity of two distinct ‘sieves’ to ensure accurate amino acid loading for proper development.
- Jiongming Lu
- , Martin Bergert
- & Beat Suter
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FGF signalling specifies haematopoietic stem cells through its regulation of somitic Notch signalling
In zebrafish embryos, Wnt and Notch signalling have been implicated in the emergence of haematopoietic stem cells during somitogenesis. Here the authors show that FGF signalling via FGFR4 acts downstream of Wnt signalling to regulate the levels of the Notch ligand DeltaC and therefore Notch pathway activity.
- Yoonsung Lee
- , Jennifer E. Manegold
- & David Traver
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| Open AccessEpigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast
Various strategies have been reported to generate mouse trophoblast stem cells (TSCs) from mouse embryonic stem cells (ESCs). Here the authors show that, regardless of the strategy used for TSC generation, these retain an epigenetic and transcriptional memory of the ESC origin and the transition remains incomplete.
- Francesco Cambuli
- , Alexander Murray
- & Myriam Hemberger
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Article
| Open AccessDNA methylation signatures link prenatal famine exposure to growth and metabolism
The long-term effect of prenatal nutrition on gene regulation is largely unknown. Here the authors identify differentially methylated regions in whole blood from individuals exposed to famine early after conception, and show that these epigenetic changes may have adverse metabolic consequences later in life.
- Elmar W. Tobi
- , Jelle J. Goeman
- & Bastiaan T. Heijmans
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Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex
Microglia colonize germinal regions of the developing cerebral cortex and contribute to the regulation of neurogenesis but the mechanisms that regulate this are not clear. Here the authors show that brain progenitor cells, through the secretion of the chemokine Cxcl12, drive microglia to cluster into the germinal regions of the developing mouse cerebral cortex.
- Benedetta Arnò
- , Francesca Grassivaro
- & Luca Muzio
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Article
| Open AccessPHD3 regulates EGFR internalization and signalling in tumours
PHD3 is a hypoxia-inducible prolyl hydroxylase that regulates stability of HIF-1. Here Garvalov et al.report a hydroxylase-independent role of PHD3 in gliomas as a scaffolding protein that promotes internalization and limits signalling of EGFR upon ligand binding, thus inhibiting growth in hypoxia.
- Boyan K. Garvalov
- , Franziska Foss
- & Till Acker
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Epithelial rotation promotes the global alignment of contractile actin bundles during Drosophila egg chamber elongation
During Drosophilaoogenesis, migration of follicle cells causes the egg chamber to rotate, changing the shape of the egg chamber from spherical to oval. Here the authors show, using live imaging, that lamellopodia on the follicle cells are required for this rotation and alignment of contractile actin bundles.
- Maureen Cetera
- , Guillermina R. Ramirez-San Juan
- & Sally Horne-Badovinac
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White matter in the older brain is more plastic than in the younger brain
Aspects of visual perception learning are known to change with age, but the associated structural correlates are poorly understood. Here the authors show that, surprisingly, visual perception in older individuals involves training-induced structural changes in white matter that are absent in younger individuals.
- Yuko Yotsumoto
- , Li-Hung Chang
- & Yuka Sasaki
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Cdo suppresses canonical Wnt signalling via interaction with Lrp6 thereby promoting neuronal differentiation
Cdo regulates early forebrain development as a co-receptor of the morphogen Shh and is required for full activation of Shh signalling. Here the authors show that Cdo interacts with the Wnt co-receptor Lrp6, thereby inhibits Wnt signalling and promotes neuronal differentiation.
- Myong-Ho Jeong
- , Seok-Man Ho
- & Jong-Sun Kang
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Article
| Open AccessThe role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice
During mouse preimplantation phases, a repressive imprint is imposed on the maternal allele of Xist, which encodes a large non-coding RNA required for X-chromosome inactivation. Here the authors show that trimethylation of histone H3 at lysine 9 on Xist promoter chromatin is responsible for the maternally determined Xistrepression.
- Atsushi Fukuda
- , Junko Tomikawa
- & Akihiro Umezawa
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NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2
N-alpha-acetyltransferase 10 (NAA10) regulates cell growth and proliferation. Here the authors show that NAA10 also has a role in osteogenesis, by fine-tuning the activity of the osteogenic transcription factor Runx2.
- Haejin Yoon
- , Hye-Lim Kim
- & Jong-Wan Park
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Tissue-specific derepression of TCF/LEF controls the activity of the Wnt/β-catenin pathway
The TCF transcription factor and the co-repressor Groucho form a repressor complex in the absence of Wnt ligand. Here the authors show that during zebrafish gastrulation, the transcription factor Lbx2 enhances Wnt/β-catenin signalling by reducing the interaction between TCF and Groucho.
- Fu-I Lu
- , Yong-Hua Sun
- & Bernard Thisse
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An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth
The Sonic hedgehog (Shh) signalling pathway plays important roles during development and its abnormal activation has been implicated in cancer. Here the authors uncover an epigenetic switch in the Shh pathway that involves the PRC2, Jmjd3/Kdm6b and Set1/MLL complexes in regulating signalling induced gene activation.
- Xuanming Shi
- , Zilai Zhang
- & Jiang Wu
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The MST1/2-SAV1 complex of the Hippo pathway promotes ciliogenesis
Although much is known about the structural and trafficking molecules involved in generation of primary cilia, the signalling proteins that regulate ciliogenesis are poorly defined. Here, Kim et al. identify the MST1/2-SAV1 complex, a core component of the Hippo pathway, as a key regulator of ciliogenesis in cells and zebrafish.
- Miju Kim
- , Minchul Kim
- & Dae-Sik Lim
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FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis
Orientation of the mitotic spindle is influenced by extracellular forces acting on the cell cortex. Here Petridou et al.identify FAK as a key transducer of mechanical forces in this context and as a result is a key regulator of spindle orientation controlling tissue architecture and morphogenesis.
- Nicoletta I. Petridou
- & Paris A. Skourides
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| Open AccessDynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease
DNA methylation is essential for proper gene expression, development and genome stability. Here the authors present whole-genome DNA methylation analyses of purified mouse cardiomyocytes from newborn, adult and failing hearts and find highly dynamic patterns between the three phenotypes of cardiomyocytes.
- Ralf Gilsbach
- , Sebastian Preissl
- & Lutz Hein
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| Open AccessCalcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts
The regulatory role of calcitonin in bone homeostasis is well studied, yet its molecular activity is poorly understood. The authors show that calcitonin regulates bone cells function by inhibiting the osteoclast secretion of sphingosine 1-phosphate, a lipid mediator of osteoclast–osteoblast crosstalk.
- Johannes Keller
- , Philip Catala-Lehnen
- & Michael Amling
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Drosophila Strip serves as a platform for early endosome organization during axon elongation
Endosomes are critical for regulating the amount and localization of cell surface molecules. Here the authors performed a genetic screen in Drosophilaand identified the protein, Strip, as a molecular linker between retrograde transport and fusion of early endosomes, which is required for axonal growth.
- Chisako Sakuma
- , Takeshi Kawauchi
- & Takahiro Chihara
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Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth
Extreme fetal growth is associated with increased risk of various adult diseases, although the mechanism underlying these associations is poorly understood. Here the authors show that abnormal fetal growth correlates with increased DNA methylation levels and report sex-specific epigenetic patterns associated with fetal growth.
- Fabien Delahaye
- , N. Ari Wijetunga
- & Francine H. Einstein
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Dynamic scaling of morphogen gradients on growing domains
Differently sized tissues follow growth patterns that are defined by morphogen gradients, but how the patterns adapt to different tissue size is unclear. Here the authors describe a computational model that can explain morphogen gradient scaling in the Drosophilawing imaginal disc and that may apply to other systems.
- Patrick Fried
- & Dagmar Iber
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Switch of PKA substrates from Cubitus interruptus to Smoothened in the Hedgehog signalosome complex
In Drosophila, protein kinase A (PKA) phosphorylates the transcription factor Cubitus interruptus (Ci) in the absence of Hedgehog signalling and the transducer Smoothened in its presence. Here, the authors investigate the mechanism underlying this switch and propose that Smoothened outcompetes Ci for association with PKA on Hedgehog signalling activation.
- Nadia Ranieri
- , Pascal P. Thérond
- & Laurent Ruel
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| Open AccessDax1 and Nanog act in parallel to stabilize mouse embryonic stem cells and induced pluripotency
The transcription factor Dax1 is often used as an embryonic stem cell (ESC) marker. Here the authors show that Dax1 acts in parallel to the pluripotency transcription factor Nanog in the maintenance of mouse ESC pluripotency and is required for full somatic cell reprogramming.
- Junlei Zhang
- , Gaoke Liu
- & Rui Jian
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Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production
Dendritic cells (DCs) initiate distinct arms of immunity in response to different classes of pathogens. Here Gringhuis et al. show that DCs produce IL-27 upon sensing fucose-containing pathogen ligands via DC-SIGN, promoting follicular T helper cell differentiation and antibody production.
- Sonja I. Gringhuis
- , Tanja M. Kaptein
- & Teunis B. H. Geijtenbeek
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Article
| Open AccessUbiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension
Biogenesis of the primary cilium begins after cell cycle exit, but the regulatory steps for its formation are poorly defined. Here the authors show that proteasome-mediated removal of the ciliogenesis inhibitor, trichoplein, from mother centrioles initiates the first step of ciliogenesis.
- Kousuke Kasahara
- , Yoshitaka Kawakami
- & Masaki Inagaki
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Out-of-frame start codons prevent translation of truncated nucleo-cytosolic cathepsin L in vivo
The lysosomal protease cathepsin L has been observed in compartments other than endosomes and lysosomes. Here the authors show using knock-in mice that nuclear localization of cathepsin L cannot be caused by N-terminal truncation of procathepsin L as previously hypothesized.
- Martina Tholen
- , Larissa E. Hillebrand
- & Thomas Reinheckel
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Bone remodelling in humans is load-driven but not lazy
Mechanical strain causes bone remodelling when it exceeds threshold levels of a proposed ‘lazy zone’, in which bone density is unresponsive to mechanical strain. Here the authors show that human bone remodeling is entirely load-driven, suggesting that no such ‘lazy’ state exists for human bones.
- Patrik Christen
- , Keita Ito
- & Bert van Rietbergen
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The subcortical maternal complex controls symmetric division of mouse zygotes by regulating F-actin dynamics
The mammalian subcortical maternal complex is composed of maternally expressed proteins and required for mouse early embryonic cell division. Here the authors show that the complex functions to control spindle positioning through regulation of the actin cytoskeleton.
- Xing-Jiang Yu
- , Zhaohong Yi
- & Lei Li
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A prominent and conserved role for YY1 in Xist transcriptional activation
X-chromosome inactivation is a tightly regulated mechanism, which silences one of the two female X chromosomes. Here Makhlouf et al. show that the autosomal transcription factor YY1 directly promotes expression of the XistRNA—a master regulator of X-chromosome inactivation—at the onset of the inactivation process.
- Mélanie Makhlouf
- , Jean-François Ouimette
- & Claire Rougeulle
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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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The ubiquitin ligase PDZRN3 is required for vascular morphogenesis through Wnt/planar cell polarity signalling
Wnt/planar cell polarity (PCP) signalling regulates angiogenesis in vertebrates. Here the authors show that the E3 ubiquitin ligase PDZRN3 ubiquitinates the PCP-signalling protein Dishevelled 3 to promote Wnt/PCP signalling, directing embryonic and postnatal remodelling of the vasculature in mouse.
- Raj N. Sewduth
- , Béatrice Jaspard-Vinassa
- & Cécile Duplàa
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Article
| Open AccessFibroblast growth factor signalling controls nervous system patterning and pigment cell formation in Ciona intestinalis
The fibroblast growth factor (FGF) signalling pathway specifies the fate of pigmented cells in the ascidian Ciona intestinalis. Here, the authors obtain lineage-specific transcription profiles of pigment precursor cells and identify FGF downstream genes involved in central nervous system patterning, and the specification and differentiation of pigmented cells.
- Claudia Racioppi
- , Ashwani K. Kamal
- & Filomena Ristoratore
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Backbone-independent nucleic acid binding by splicing factor SUP-12 reveals key aspects of molecular recognition
Alternative splicing is a widespread mechanism used in the control of gene expression during development. Here, Amrane et al.provide molecular level insights into how the RRM-domain muscle-specific factor SUP-12 interacts with its nucleic acid substrates to direct splicing patterns.
- Samir Amrane
- , Karine Rebora
- & Cameron D Mackereth
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Article
| Open AccessNucleosomal occupancy changes locally over key regulatory regions during cell differentiation and reprogramming
Changes in chromatin structure impact gene expression programs by modulating accessibility to the transcription machinery. Here, West et al. explore differences in nucleosome occupancy between mammalian pluripotent and somatic cells and uncover regulatory regions likely to play key roles in determining cell identity.
- Jason A. West
- , April Cook
- & Robert E. Kingston
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Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis
Tumour angiogenesis is critical for tumour growth and metastasis but the mechanisms that promote the growth of new blood vessels by tumours are not completely clear. Here the authors show that overexpression of the transcription factor Twist1 in certain tumour cells can lead them to differentiate into endothelial cells.
- Hsiao-Fan Chen
- , Chi-Hung Huang
- & Kou-Juey Wu
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A metabolic view on menopause and ageing
Changes in serum metabolites can indicate the development of disease. Here, the authors measure serum metabolite and lipoprotein levels in a large cohort of Northern Europeans, creating metabolic fingerprints for various age groups and, specifically, for women at the onset of menopause.
- Kirsi Auro
- , Anni Joensuu
- & Markus Perola
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The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells
Mutations in the deubiquitinase gene CYLD are associated with cylindromatosis, a disease characterized by the development of skin appendage tumours. Eguether et al.discover that CYLD localizes to centrosomes and is required for basal body migration and docking, providing insight into its tumour suppressor activity.
- Thibaut Eguether
- , Maria A. Ermolaeva
- & Anne-Marie Tassin
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miR-195/497 induce postnatal quiescence of skeletal muscle stem cells
Skeletal muscle stem cells are in a state of cell cycle arrest in adult skeletal muscles and are stimulated to proliferate and differentiate in response to injury or pathology. Here the authors identify two microRNAs, miR-195 and miR-497, which induce cell cycle arrest in the stem cells and suppress myogenesis.
- Takahiko Sato
- , Takuya Yamamoto
- & Atsuko Sehara-Fujisawa
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YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression
Lung adenocarcinomas can convert to squamous cell carcinomas, which is associated with cancer progression and therapy resistance. Here, Gao et al. identify YAP as an essential barrier for this phenotypic conversion through ZEB2-mediated DNP63 repression.
- Yijun Gao
- , Wenjing Zhang
- & Hongbin Ji
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Article
| Open AccessMyocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart
The secreted ligand Angiopoietin-1 is essential for embryonic blood vessel development and adult vascular homeostasis. Here the authors show, using conditional knockout mice, that myocardium-derived Angiopoietin-1 is required for the formation of coronary veins, but not arteries.
- Yoh Arita
- , Yoshikazu Nakaoka
- & Issei Komuro
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PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1
Loss of function of the kinase PINK1 is associated with familial early-onset Parkinson’s disease and impaired clearance of damaged mitochondria. Here the authors show that the resulting oxidative stress activates the hypoxia regulator HIF1α, resulting in increased glycolysis and cell proliferation.
- Raquel Requejo-Aguilar
- , Irene Lopez-Fabuel
- & Juan P. Bolaños
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Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells
Prostate epithelia contain basal, luminal and neuroendocrine cells. Here the authors show that overexpression of the Notch intracellular domain in the mouse prostate promotes proliferation and suppresses anoikis of prostate luminal epithelial cells.
- Oh-Joon Kwon
- , Joseph M. Valdez
- & Li Xin
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WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors
The transcription factor Wilms’ tumour 1 (WT1) regulates kidney development, and Wt1 mutations are associated with renal cancer. Here the authors identify WT1 target genes in renal progenitors during early kidney development in mouse embryos and show that loss of Wt1suppresses FGF and induces BMP signalling.
- Fariba Jian Motamedi
- , Danielle A. Badro
- & Andreas Schedl
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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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Article
| Open Access3D niche microarrays for systems-level analyses of cell fate
3D cell culture matrices more closely resemble the natural microenvironments of stem cells than 2D systems. Here, the authors present a 3D cell culture approach to screen for the influence of environmental parameters on self-renewal and differentiation of single mouse embryonic stem cells.
- A. Ranga
- , S. Gobaa
- & M. P. Lutolf
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