Featured
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| Open AccessFunctional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation
Trophoblast stem cells can be derived from human blastocysts and first-trimester, but not term, cytotrophoblasts. Here the authors show that induction efficiency of cytotrophoblast is determined by antagonism between GCM1 and ΔNp63α and manipulating this antagonism facilitates derivation of TS cells from term placenta.
- Liang-Jie Wang
- , Chie-Pein Chen
- & Hungwen Chen
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Article
| Open AccessMalfunction of airway basal stem cells plays a crucial role in pathophysiology of tracheobronchopathia osteoplastica
Tracheobronchopathia osteoplastica (TO), is an underreported affliction characterized by squamous metaplasia and heterotopic bone formation in trachea and bronchi. Here the authors apply functional, as well as genome-wide transcriptional and epigenetic profiling to identify airway basal cells dysfunction underlying TO.
- Yue Hong
- , Shan Shan
- & Tao Ren
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Article
| Open AccessGeneration of the organotypic kidney structure by integrating pluripotent stem cell-derived renal stroma
Organs consist of parenchyma and stroma. Nishinakamura and colleagues induce renal stromal progenitors from mouse pluripotent stem cells (PSCs), and generate completely PSC-derived organoids that reproduce complex kidney structure.
- Shunsuke Tanigawa
- , Etsuko Tanaka
- & Ryuichi Nishinakamura
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Article
| Open AccessParallel functional assessment of m6A sites in human endodermal differentiation with base editor screens
N6-methyladenosine (m6A) plays important role in lineage specifications of embryonic stem cells, but its role at specific sites has not been assessed. Here the authors develop an adenine editor-based strategy, and systematically identify functional m6A sites that control lineage decisions in human embryonic stem cells.
- Weisheng Cheng
- , Fang Liu
- & Jinkai Wang
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Article
| Open AccessTranscriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants
Coordinated programs of gene expression drive brain development. Here, the authors use human embryonic stem cells and foetal cortical tissue as well as available GWAS statistics and analysis of genetic variants associated with neuropsychiatric disorders and cognition revealing a convergence on transcriptional programs regulating excitatory cortical neurogenesis.
- Bret Sanders
- , Daniel D’Andrea
- & Eunju Shin
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Article
| Open AccessRobust differentiation of human enteroendocrine cells from intestinal stem cells
Hormone-producing enteroendocrine cells (EEC) regulate of energy homeostasis and gastrointestinal function. Here the authors report protocols to induce human intestinal stem cells into EECs producing multiple gut hormones, including SST, 5-HT, CCK and GIP, using directed differentiation with small molecules targeting FOXO1, JNK and CB1 signalling.
- Daniel Zeve
- , Eric Stas
- & David T. Breault
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Article
| Open AccessDiscrete regulatory modules instruct hematopoietic lineage commitment and differentiation
Lineage differentiation and commitment is driven by transcription regulators and chromatin changes. Here the authors report daily profiling of chromatin accessibility and transcriptome changes during human erythropoiesis, relating these changes to lineage potential between erythropoiesis and megakaryopoieis.
- Grigorios Georgolopoulos
- , Nikoletta Psatha
- & Jeff Vierstra
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Article
| Open AccessAn integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation
To characterize molecular changes during cell type transitions, the authors develop a method to simultaneously measure protein expression and thermal stability changes. They apply this approach to study differences between human pluripotent stem cells, their progenies, parental and allogeneic cells.
- Pierre Sabatier
- , Christian M. Beusch
- & Roman A. Zubarev
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Article
| Open AccessGain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies
Mutations in the splicing factor RBM20 cause aggressive Dilated Cardiomyopathy. Here the authors generated RBM20 R636S mutants and knockout in human iPSC-derived cardiomyocytes. Mutant RBM20 showed different target RNA binding, altered splicing and localization to cytoplasmic processing bodies.
- Aidan M. Fenix
- , Yuichiro Miyaoka
- & Nathan Salomonis
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Article
| Open AccessVariant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes
Polycomb repressive complexes (PRC1 and PRC2) repress genes that are crucial for development via epigenetic modifications; however, their role in differentiation is not well known. Here the authors reveal that a PCGF1-containing PRC1 variant facilitates exit from pluripotency by downregulating target genes and recruiting PRC2.
- Hiroki Sugishita
- , Takashi Kondo
- & Haruhiko Koseki
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Article
| Open AccessSelf-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.
- Yonatan R. Lewis-Israeli
- , Aaron H. Wasserman
- & Aitor Aguirre
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Article
| Open AccessBioengineered embryoids mimic post-implantation development in vitro
Previous approaches to derive embryoids either lack physiological morphology and signaling interactions, or are unconducive to model post-gastrulation development. Here the authors use a high-throughput approach to induce mouse embryonic stem cells into epiblast-like aggregates, which are then co-cultured with mouse trophoblast stem cell aggregates, to yield embryoids with axial morphogenesis and anterior development.
- Mehmet U. Girgin
- , Nicolas Broguiere
- & Matthias P. Lutolf
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Article
| Open AccessAmnion signals are essential for mesoderm formation in primates
Human and murine embryonic development has disparities, highlighting the need for primate systems. Here, the authors construct a post-implantation transcriptional atlas from non-human primate embryos and show ISL1 controls a gene regulatory network in the amnion required for mesoderm formation.
- Ran Yang
- , Alexander Goedel
- & Kenneth R. Chien
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Article
| Open AccessA TALE/HOX code unlocks WNT signalling response towards paraxial mesoderm
Cells in the developing embryo interpret WNT signalling with context-dependence, but the mechanism decoding these cues is unclear. Here, the authors show that combinatorial TALE/HOX activity destabilizes nucleosomes at WNT-responsive regions to activate paraxial mesodermal genes.
- Luca Mariani
- , Xiaogang Guo
- & Elisabetta Ferretti
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Article
| Open AccessGrafting of iPS cell-derived tenocytes promotes motor function recovery after Achilles tendon rupture
Tendon self-renewal occurs rarely and reconstructive surgery comes with significant limitations. Here the authors present an induced pluripotent stem cell-based method to generate tenocytes, analyze their developmental trajectory using scRNA-seq, and demonstrate their contribution to motor function recovery after Achilles tendon injury via engraftment and paracrine effects.
- Taiki Nakajima
- , Akihiro Nakahata
- & Makoto Ikeya
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Article
| Open AccessHuman iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro
The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.
- Jun Jie Tan
- , Jacques P. Guyette
- & Harald C. Ott
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Article
| Open AccessLabel-free imaging for quality control of cardiomyocyte differentiation
Differentiation of hPSCs to cardiomyocytes suffers from high variability. Here the authors report a label-free live cell imaging platform based on autofluorescence imaging to enable the prediction of cardiomyocyte differentiation efficiency from hPSCs.
- Tongcheng Qian
- , Tiffany M. Heaster
- & Melissa C. Skala
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Article
| Open AccessTranscriptional profiling of mESC-derived tendon and fibrocartilage cell fate switch
The transcriptional regulators underlying the induction and differentiation of dense connective tissues remain largely unknown. Here the authors generate tendon and fibrocartilage cells from mouse embryonic stem cells and apply scRNA-seq to identify molecular regulation of the cell fate switch between these lineages.
- Deepak A. Kaji
- , Angela M. Montero
- & Alice H. Huang
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Article
| Open AccessERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERRγ agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.
- Kenji Miki
- , Kohei Deguchi
- & Yoshinori Yoshida
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Article
| Open AccessDecreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells
Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.
- Blaise Su Jun Low
- , Chang Siang Lim
- & Adrian Kee Keong Teo
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Article
| Open AccessA 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion
From single-cell transcriptome analyses to defining culture media for spheroids, the authors provide a census of information to understand the development of human pancreatic progenitors. This approach identifies signalling pathways (EGF and FGF) regulating progenitor proliferation.
- Carla A. Gonçalves
- , Michael Larsen
- & Anne Grapin-Botton
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Article
| Open AccessG-quadruplexes originating from evolutionary conserved L1 elements interfere with neuronal gene expression in Alzheimer’s disease
G-quadruplexes (G4) can be formed from DNA sequences containing consecutive guanines organized in 4-interspaced tandem repeats. Here the authors reveal the association between G4 structures present at specific loci in Alzheimer’s disease neurons and reduced gene expression and perturbed alternative splicing.
- Roy Hanna
- , Anthony Flamier
- & Gilbert Bernier
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Article
| Open AccessNutrient restriction synergizes with retinoic acid to induce mammalian meiotic initiation in vitro
Retinoic acid is necessary but not sufficient to induce meiosis. Here, the authors use primary mouse undifferentiated spermatogonia culture to show that nutrient restriction, an inducer of yeast meiosis, combined with retinoic acid induces meiotic gene and chromosome programs in mammalian germ cells.
- Xiaoyu Zhang
- , Sumedha Gunewardena
- & Ning Wang
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Article
| Open AccessPlasmodium vivax infection compromises reticulocyte stability
During Plasmodium intra-erythrocytic developmental, parasites compromise the structural integrity of host red-blood cells. Here, Clark et al. develop a flow cytometric osmotic stability assay to show that P. vivax infection destabilizes host reticulocytes, which are less stable than P. falciparum-infected normocytes.
- Martha A. Clark
- , Usheer Kanjee
- & Manoj T. Duraisingh
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Article
| Open AccessPGC1/PPAR drive cardiomyocyte maturation at single cell level via YAP1 and SF3B2
Cardiomyocyte maturation and the acquisition of phenotypes is poorly understood at the single cell level. Here, the authors analyse the transcriptome of single cells from neonatal to adult heart and reveal that peroxisome proliferator-activated receptor coactivator-1 mediates the phenotypic shift.
- Sean A. Murphy
- , Matthew Miyamoto
- & Chulan Kwon
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Article
| Open AccessSPT6 promotes epidermal differentiation and blockade of an intestinal-like phenotype through control of transcriptional elongation
The role of RNA polymerase II (Pol II) recruitment during adult stem cell differentiation is well understood, but not that of Pol II elongation. Here, the authors show that 30% of epidermal stem cell differentiation genes depend on SPT6 and PAF1 for Pol II elongation, and SPT6 loss leads to an intestine-like phenotype.
- Jingting Li
- , Xiaojun Xu
- & George L. Sen
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Article
| Open AccessMINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia
Tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, the authors describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the MINPP1 gene, characterised by intracellular imbalance of inositol polyphosphate metabolism.
- Ekin Ucuncu
- , Karthyayani Rajamani
- & Vincent Cantagrel
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Article
| Open AccessSTRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells
STRAP (serine threonine kinase receptor-associated protein) promotes tumorigenicity. Here the authors report that STRAP associates with spliceosome and regulates alternative splicing during embryonic stem cell lineage commitment and early mouse embryo organogenesis.
- Lin Jin
- , Yunjia Chen
- & Pran K. Datta
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Article
| Open AccessTransplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice
Pericytes play an essential role in blood brain barrier (BBB) integrity. Here, the authors generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) which display functional properties and also promote BBB recovery in a mouse model of cerebral artery occlusion.
- Jiaqi Sun
- , Yinong Huang
- & Weiqiang Li
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Article
| Open AccessDOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility
Neuronal differentiation requires rearrangement of the transcriptional and chromatin landscapes of neural cells. Here, the authors study in-vitro neuronal differentiation of murine embryonic stem cells (ESCs) to show that this process is modulated by DOT1L activity, which regulates H3K79me2 accumulation, and preserves accessibility of SOX2-bound enhancers.
- Francesco Ferrari
- , Laura Arrigoni
- & Thomas Manke
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Article
| Open AccessPlatelet-derived microparticles enhance megakaryocyte differentiation and platelet generation via miR-1915-3p
Platelets derive from megakaryocytes, which differentiate from hematopoietic stem/progenitor cells (HSPCs). Here, Qu et al show that platelet-derived microparticles carrying miR-1915-3p target HSPCs and promote megakaryopoiesis by suppressing RHOB expression levels.
- Mingyi Qu
- , Xiaojing Zou
- & Xuetao Pei
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Article
| Open AccessSingle cell transcriptomics identifies a signaling network coordinating endoderm and mesoderm diversification during foregut organogenesis
The fetal murine foregut develops into visceral organs via interactions between the mesoderm and endoderm, but how is unclear. Here, the authors use single cell RNAseq to show a diversity in organ specific splanchnic mesoderm cell-types, infer a signalling network governing organogenesis and use this to differentiate human pluripotent stem cells.
- Lu Han
- , Praneet Chaturvedi
- & Aaron M. Zorn
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Article
| Open AccessPre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease
Induced pluripotent stem cell (iPSC) derived dopaminergic neurons are a promising source for cell-based Parkinson’s disease (PD) therapy. Here the authors report a comprehensive pre-clinical evaluation of the safety and efficacy of dopaminergic progenitors derived from a clinical-grade human iPSC line.
- Daisuke Doi
- , Hiroaki Magotani
- & Jun Takahashi
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Article
| Open AccessADNP promotes neural differentiation by modulating Wnt/β-catenin signaling
ADNP has been connected to neural developmental disorders. Here, the authors uncover a role for ADNP in neural induction and differentiation via β-Catenin stabilization, with ADNP disruption in zebrafish leading to defective neurogenesis and decreased Wnt signaling.
- Xiaoyun Sun
- , Xixia Peng
- & Yuhua Sun
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Article
| Open AccessLoss of the transcription factor MAFB limits β-cell derivation from human PSCs
The MAF bZIP transcription factor B (MAFB) is present in postnatal human beta cells but its role is unclear. Here, the authors show that MAFB regulates endocrine pancreatic cell fate specification.
- Ronan Russell
- , Phichitpol P. Carnese
- & Matthias Hebrok
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Article
| Open AccessDissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium
Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft-like progenitor for pulmonary neuroendocrine cells and ionocytes.
- Katherine C. Goldfarbmuren
- , Nathan D. Jackson
- & Max A. Seibold
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Article
| Open AccessA method for the generation of human stem cell-derived alpha cells
Deriving functional pancreatic cell types from human stem cells may have important clinical applications. Building on previous work, here the authors generate stem cell-derived alpha cells via a polyhormonal intermediate, which have a gene expression pattern similar to human islet alpha cells and behave as such when transplanted into mice.
- Quinn P. Peterson
- , Adrian Veres
- & Douglas A. Melton
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Article
| Open AccessHighly parallel and efficient single cell mRNA sequencing with paired picoliter chambers
Single-cell RNA-seq can reveal accurate and precise cell types and states. Here the authors present an scRNA-seq platform, Paired-seq, which uses differential flow resistance to achieve 95% cell utilisation efficiency for improved cell-free RNA removal and gene detection.
- Mingxia Zhang
- , Yuan Zou
- & Chaoyong Yang
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Article
| Open AccessEngineered niches support the development of human dendritic cells in humanized mice
Classical human dendritic cells (cDCs) are rare sentinel cells specialized in regulating adaptive immunity. Here, the authors show that expression of membrane bound FLT3L, along with stem cell factor (SCF) and CXCL12 in stromal cells induces specification of pre/AS-DCs, type 1 and type2 cDC from haematopoietic stem cells.
- Giorgio Anselmi
- , Kristine Vaivode
- & Pierre Guermonprez
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Article
| Open AccessStem cell-derived polarized hepatocytes
To model hepatocyte function accurately in vitro, it is necessary to generate and maintain a polarized epithelium. Here, the authors describe a protocol to generate polarized human pluripotent stem cell-derived hepatocyte-like cells (HLCs) to model enteric virus production and drug secretion in vitro.
- Viet Loan Dao Thi
- , Xianfang Wu
- & Charles M. Rice
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Article
| Open AccessAmino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines
Hepatocytes grown in a dish are immature and do not metabolize compounds as a real liver would. Here, the authors supply stem cell-derived hepatocytes with amino acids at a higher concentration than nutritionally necessary, changing the metabolism of these cells, making them more mature and useful for drug screening and toxicity studies.
- Ruben Boon
- , Manoj Kumar
- & Catherine M. Verfaillie
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Article
| Open AccessThe in vivo genetic program of murine primordial lung epithelial progenitors
The identity of the earliest murine in vivo lung epithelial progenitors (marked by NKX2-1 expression) is unclear. Here, the authors use single-cell RNA sequencing to define the genetic program of these lung primordial progenitors, which will improve in vitro lung specification of pluripotent stem cells.
- Laertis Ikonomou
- , Michael J. Herriges
- & Darrell N. Kotton
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Article
| Open AccessJMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells
Neurogenesis is an ordered transition from pluriptotent cells to neural precursor cells (NPCs) to neurons. Here the authors show that loss of the lysine demethylases JMJD3 and UTX leads reduced DNA accessibility at neurogenesis loci in human NPCs, and that the chromatin remodeller BAF can rescue differentiation defects.
- Yongli Shan
- , Yanqi Zhang
- & Guangjin Pan
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Article
| Open AccessGeneration of mesenchyme free intestinal organoids from human induced pluripotent stem cells
Human induced pluripotent stem cell-derived intestinal organoids (HIOs) are powerful tools to study development and diseases of the gastrointestinal tract. Here, the authors develop a directed differentiation protocol to generate mesenchyme-free HIOs that can be patterned towards proximal small intestine or colonic epithelium, and demonstrated their utility in modeling CFTR function.
- Aditya Mithal
- , Amalia Capilla
- & Gustavo Mostoslavsky
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Article
| Open AccessProx1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche
Acetylcholine regulates intestinal epithelial secretion via muscarinic Gq-coupled receptors but its role in cell differentiation is unclear. Here, the authors show that Prox1-positive endocrine cells are sensors for the cholinergic intestinal niche and can trigger increased differentiation of enteroendocrine DCLK1-positive tuft cells.
- Moritz Middelhoff
- , Henrik Nienhüser
- & Timothy C. Wang
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Article
| Open AccessSingle cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation
How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.
- Ayshwarya Subramanian
- , Eriene-Heidi Sidhom
- & Anna Greka
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Article
| Open AccessSuper-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells
Trophectoderm lineage development is essential for implantation, placentation, and healthy pregnancy. Here the authors map super-enhancers (SEs) in trophoblast stem cells and find both TE-specific master regulators and 150 previous uncharacterised transcription factors that are SE-associated, providing insight into trophectoderm-specific regulatory networks.
- Bum-Kyu Lee
- , Yu jin Jang
- & Jonghwan Kim
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Article
| Open AccessDifferential regulation of OCT4 targets facilitates reacquisition of pluripotency
Barriers underlying the inefficiency of reprogramming cells to pluripotency are poorly defined. Here the authors identify a transient interval soon after pluripotency exit that permits high-efficiency reprogramming and is facilitated by OCT4 bound elements displaying unique silencing behaviour during differentiation.
- Sudhir Thakurela
- , Camille Sindhu
- & Alexander Meissner
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Article
| Open AccessThe WT1-like transcription factor Klumpfuss maintains lineage commitment of enterocyte progenitors in the Drosophila intestine
Notch signaling mediates intestinal enteroblast specification in Drosophila but the molecular mechanism as to how this is regulated is unclear. Here, the authors show that the transcription factor Klumpfuss ensures enteroblast commitment through repression of enteroendocrine cell fate downstream of Notch.
- Jerome Korzelius
- , Sina Azami
- & Heinrich Jasper