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| Open AccessTranscription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
Transcription Factor 4 (TCF4) has been associated with autism and schizophrenia. Here, the authors demonstrate aberrant proliferation and differentiation in neural cells and organoids carrying mutations in TCF4.
- Fabio Papes
- , Antonio P. Camargo
- & Alysson R. Muotri
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| Open AccessRegulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity
Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.
- Reuben Franklin
- , Yiming Guo
- & Sihem Cheloufi
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| Open AccessPeriodic formation of epithelial somites from human pluripotent stem cells
Somitogenesis has been well characterized in model organisms, resulting in detailed description of the somite segmentation clock. Here they generate somitogenic organoids from human pluripotent stem cells that recapitulate somitogenesis, periodic segmentation, and proper polarity.
- Marina Sanaki-Matsumiya
- , Mitsuhiro Matsuda
- & Miki Ebisuya
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| Open AccessCell-lineage controlled epigenetic regulation in glioblastoma stem cells determines functionally distinct subgroups and predicts patient survival
The epigenetic regulation of glioblastoma stem cell (GSC) function remains poorly understood. Here, the authors compare the chromatin accessibility landscape of GSC cultures from mice and patients and suggest that the epigenome of GSCs is cell lineage-regulated and could predict patient survival.
- Xi Lu
- , Naga Prathyusha Maturi
- & Xingqi Chen
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| Open AccessSingle cell analyses identify a highly regenerative and homogenous human CD34+ hematopoietic stem cell population
The trajectories of hematopoietic stem cells (HSCs) during lineage commitment are complex. Here, the authors use single cell RNA-sequencing and xenotransplantation to uncover CD34 + EPCR + (CD38/CD45RA)- HSCs, which high repopulating and self-renewal properties.
- Fernando Anjos-Afonso
- , Florian Buettner
- & Dominique Bonnet
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| Open AccessDifferential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model
Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro.
- Qizhou Lian
- , Kui Zhang
- & Huanhuan Joyce Chen
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Article
| Open AccessCHD7 regulates bone-fat balance by suppressing PPAR-γ signaling
CHD7 is chromatin remodeler and mutations of CHD7 are the main cause of CHARGE syndrome. Here the authors show that conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and pre-osteoblasts leads to a skeletal system development disorder in mice and upregulated PPAR signaling, disrupting the balance between osteogenic and adipogenic differentiation.
- Caojie Liu
- , Qiuchan Xiong
- & Ning Kang
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Article
| Open AccessThe nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation
Mature cardiac muscle requires high mitochondrial ATP production and specialized contractile proteins. Here the authors demonstrate that cardiomyocyte-specific contractile maturation involves cooperation between the nuclear receptor ERRγ and cardiogenic transcription factor GATA4, but ERRγ controls metabolic genes independently.
- Tomoya Sakamoto
- , Kirill Batmanov
- & Daniel P. Kelly
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Article
| Open AccessHuman pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling
In vitro differentiation of pancreatic beta cells offers a potential therapeutic approach for diabetes. Here they show human pluripotent stem cell derived pancreatic progenitors differentiate into insulin-secreting cells by crosstalk of WNT5A and BMP signaling.
- Jolanta Chmielowiec
- , Wojciech J. Szlachcic
- & Malgorzata Borowiak
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Article
| Open AccessElastic dosage compensation by X-chromosome upregulation
The concerted dynamics of X-chromosome upregulation and X-chromosome inactivation, which collectively balance X-chromosome expression, are not well understood. Using allelic single-cell genomics, the authors characterize the dynamics of X-chromosome upregulation and inactivation along mouse embryonic and stem cell development, calling to question keys aspects of the established model of mammalian dosage compensation.
- Antonio Lentini
- , Huaitao Cheng
- & Björn Reinius
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| Open AccessCell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells
Rapid intestinal regeneration after injury is critical to maintain barrier integrity and homeostasis, but must be tightly controlled to prevent tumorigenesis. Here they show that the aryl hydrocarbon receptor is required to terminate the regenerative response after wound healing.
- Kathleen Shah
- , Muralidhara Rao Maradana
- & Brigitta Stockinger
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Article
| Open AccessTissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids
The culture of gastrointestinal organoids relies on Matrigel that has several drawbacks for clinical application. Here, the authors report the feasibility of gastrointestinal tissue-mimetic matrices as effective alternatives to Matrigel for organoid culture and transplantation.
- Suran Kim
- , Sungjin Min
- & Seung-Woo Cho
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Article
| Open AccessBAF complex-mediated chromatin relaxation is required for establishment of X chromosome inactivation
Female embryonic stem cells (ESCs) are the ideal model to study X chromosome inactivation (XCI) establishment; however, these cells are challenging to keep in culture. Here the authors create fluorescent ‘Xmas’ reporter mice as a renewable source of ESCs and show nucleosome remodelers Smarcc1 and Smarca4 create a nucleosome-free promoter region prior to the establishment of silencing.
- Andrew Keniry
- , Natasha Jansz
- & Marnie E. Blewitt
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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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| Open AccessEngineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics
Here, the authors use single cell RNA-sequencing to generate an atlas of signaling interactions regulating embryonic hematopoietic stem cell (HSC) development and apply this knowledge to engineer a niche sufficient to support HSC maturation in vitro.
- Brandon Hadland
- , Barbara Varnum-Finney
- & Irwin D. Bernstein
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Article
| Open AccessBMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation
Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here the authors identify a BMP feedback loop between the stomach epithelium and surrounding stroma that controls gland homeostasis and demonstrate its interruption upon infection with H. pylori.
- Marta Kapalczynska
- , Manqiang Lin
- & Michael Sigal
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Article
| Open AccessSpatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium
Rapid turnover and regeneration of intestinal epithelium requires distinct intestinal stem cell (ISC) populations. Here the authors show p57 marks quiescent ISCs, and that differentiated cells revert to stem cell state after injury, through dynamic reprogramming characterized by fetal- and metaplastic-like changes.
- Tsunaki Higa
- , Yasutaka Okita
- & Keiichi I. Nakayama
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| Open AccessA non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine
Metabolic reprogramming upon SIRT6 loss induces tumour formation in the intestine but the mechanism is unclear. Here, the authors show that loss of SIRT6 leads to the expansion of epithelial cells with high pyruvate dehydrogenase kinase activity resulting in enhanced stem cell activity and tumour-initiating potential
- Carlos Sebastian
- , Christina Ferrer
- & Raul Mostoslavsky
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| Open AccessMassively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation
How gene regulatory elements regulate gene expression during cellular differentiation remains largely unknown. Here the authors use perturbation-based massively parallel reporter assays at early time points of neural differentiation to systematically characterize how regulatory elements and motifs within them guide different transcriptional patterns.
- Anat Kreimer
- , Tal Ashuach
- & Nadav Ahituv
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| Open AccessPrimary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging
Repair of muscle damage requires muscle stem cells, which lose regenerative capacity with aging. Here, the authors show that a sensory organelle, the primary cilium, is critical for muscle stem cell proliferation during regeneration and lost with aging.
- Adelaida R. Palla
- , Keren I. Hilgendorf
- & Helen M. Blau
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| Open AccessGpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency
Gpr125 has emerged as a specific marker of mammary stem cells and basal progenitors. Here they show that Gpr125 cells congregate at ductal tips during morphogenesis and amass at tumor margins, and that high Gpr125 predicts early tumor onset and poor outcome in basal breast cancer.
- Elena Spina
- , Julia Simundza
- & Pamela Cowin
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| Open AccessElectrical modulation of transplanted stem cells improves functional recovery in a rodent model of stroke
Paul George and colleagues developed a conductive polymer system to enable stem cell delivery and electrical modulation in vivo. Employing this system improved functional stroke recovery in rodents and identified important repair pathways.
- Byeongtaek Oh
- , Sruthi Santhanam
- & Paul M. George
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| 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 AccessA specialized bone marrow microenvironment for fetal haematopoiesis
The colonization of bone marrow by haematopoietic stem and progenitor cells is critical for lifelong blood cell formation. Here the authors report distinct features of fetal bone marrow and show that artery-derived signals promote haematopoietic colonization.
- Yang Liu
- , Qi Chen
- & Ralf H. Adams
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| Open AccessA systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders
Ex-vivo gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising treatment for monogenic diseases. Here the authors report a systematic review and meta-analysis of available evidence assessing clinical outcomes of HSPC gene therapy from clinical trials.
- Francesca Tucci
- , Stefania Galimberti
- & Alessandro Aiuti
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| Open AccessComprehensive 3D epigenomic maps define limbal stem/progenitor cell function and identity
Genome topology provides a structural basis for epigenome-mediated transcriptional regulation in eukaryotes. Here the authors characterized the 3D genome of stratified squamous epithelia. They generated a Hi-C map of human limbal stem/progenitor cells (LSCs) and integrated these data with epigenomics, transcription factor binding maps, and transcriptome data.
- Mingsen Li
- , Huaxing Huang
- & Hong Ouyang
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| Open AccessA comprehensive temporal patterning gene network in Drosophila medulla neuroblasts revealed by single-cell RNA sequencing
During development, neural progenitors generate a variety of neural types sequentially. Here the authors examine gene expression patterns in Drosophila neural progenitors at single-cell level, and identify a gene regulatory network controlling the sequential generation of different neural types.
- Hailun Zhu
- , Sihai Dave Zhao
- & Xin Li
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Article
| Open AccessCytonemes coordinate asymmetric signaling and organization in the Drosophila muscle progenitor niche
Asymmetric signaling and organization in the stem cell niche determine cell fates. Here the authors show that polarized contact-dependent signaling through specialized cytonemes forms the basis of niche-specific asymmetric signaling and stem cell organization.
- Akshay Patel
- , Yicong Wu
- & Sougata Roy
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Article
| Open AccessTig1 regulates proximo-distal identity during salamander limb regeneration
The mechanisms by which cells determine their position within the 3D space are poorly understood. Research in salamanders offers fresh insights into this question, uncovering Tig1 as a central determinant of proximo-distal identity in regeneration.
- Catarina R. Oliveira
- , Dunja Knapp
- & Maximina H. Yun
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| Open AccessMulti-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment
During human embryonic development, haematopoietic stem cells of the foetal liver undergo expansion, while retaining engraftment capacity. Here the authors apply CITE-seq to profile single cells from a human foetal liver, identifying a molecular signature of engraftment potential
- Kim Vanuytsel
- , Carlos Villacorta-Martin
- & George J. Murphy
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| Open AccessModelling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming
Here, Koster et al., model human papillomavirus and Chlamydia coinfection dynamics in patient-derived ectocervical organoids, and characterize the effects of multiple infections in the cellular microenvironment, potentially contributing to neoplasia.
- Stefanie Koster
- , Rajendra Kumar Gurumurthy
- & Cindrilla Chumduri
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Article
| Open AccessSingle-cell profiling of human subventricular zone progenitors identifies SFRP1 as a target to re-activate progenitors
The decline in neurogenesis following birth is accompanied with a quiescent state characteristic of neural progenitors of the adult brain. Here, the authors identify the Wnt pathway antagonist SFRP1 as a potential signal that promotes quiescence and show that its inhibition stimulates stem cell activation.
- Vanessa Donega
- , Astrid T. van der Geest
- & Elly M. Hol
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| Open AccessCPEB1 directs muscle stem cell activation by reprogramming the translational landscape
Skeletal muscle stem cells are actively maintained in quiescence, but can activate quickly upon extrinsic stimulation. Here the authors show that CPEB1 promotes muscle stem cell activation by reprogramming the translational landscape.
- Wenshu Zeng
- , Lu Yue
- & Tom H. Cheung
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Article
| Open AccessMesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity
Regulatory T (Treg) cells and mesenchymal stem cells (MSCs) are both cell populations capable of immune tolerance induction. Here the authors show that the transfer of mitochondria from mesenchymal stem cells to allogeneic Treg cells in an HLA-dependent manner results in enhanced immunosuppressive functions of Treg cells.
- Karolina Piekarska
- , Zuzanna Urban-Wójciuk
- & Natalia Maria Marek-Trzonkowska
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Article
| Open AccessEnhanced germline stem cell longevity in Drosophila diapause
Drosophila enter adult reproductive diapause in low temperatures and short day, halting ovarian development yet preserving fertility. Here the authors show that ovarian arrest in diapause is distinct from other stress responses and that despite DNA damage and decreased division, germline stem cells recover.
- Sreesankar Easwaran
- , Matthew Van Ligten
- & Denise J. Montell
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| Open AccessMesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling
The small intestine forms via crosstalk between epithelial and mesenchymal cell compartments. Here, the authors show that a gradient of Wnt signalling along the anterior-posterior axis regulates Sonic Hedgehog which is required for correct formation and regionalization of the small intestine.
- Martti Maimets
- , Marianne Terndrup Pedersen
- & Kim B. Jensen
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| Open AccessLima1 mediates the pluripotency control of membrane dynamics and cellular metabolism
How pluripotency transcription factors regulate the cellular architecture and energetics has remained largely unknown. Here the authors identify Lima1 as a key effector that mediates the pluripotency control of membrane dynamics and cellular metabolism.
- Binyamin Duethorn
- , Fabian Groll
- & Ivan Bedzhov
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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 AccessCholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis
The sympathetic nervous system has been shown to respond to stress and activate haematopoietic stem cells. Here they show that cholinergic signals in the bone marrow preserve haematopoietic stem cell quiescence and self-renewal under proliferative stress.
- Claire Fielding
- , Andrés García-García
- & Simón Méndez-Ferrer
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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 AccessExpression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids
The study of human microglia function in health and disease is limited by the availability of sound models. Here, the authors develop a method to generate functional microglia in human cortical organoids and investigate the role of human microglia during amyloid beta1-42- induced inflammation.
- Bilal Cakir
- , Yoshiaki Tanaka
- & In-Hyun Park
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Article
| Open AccessQuantification of bone marrow interstitial pH and calcium concentration by intravital ratiometric imaging
The fate of hematopoietic stem cells can be controlled by factors such as calcium ion concentration. Here the authors report an intravital ratiometric analysis method to measure extracellular calcium ion concentrations and absolute pH in mouse bone marrow.
- S-C. A. Yeh
- , J. Hou
- & C. P. Lin
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Article
| Open AccessPre-configuring chromatin architecture with histone modifications guides hematopoietic stem cell formation in mouse embryos
Here, the authors employed Hi-C and low-input itChIP-seq in four rare populations of the hematopoietic stem cell (HSC) ontogeny trajectory across early arterial endothelial cells (eAECs), hemogenic endothelial cells (HECs), pre-HSCs, and long-term HSCs (LT-HSCs) from mouse embryos to show that active histone modifications are largely set up in eAECs and 3D genome is then subsequently configured.
- Chen C. Li
- , Guangyu Zhang
- & Aibin He
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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 AccessMyoD is a 3D genome structure organizer for muscle cell identity
Pioneer transcription factors (TFs) have been proposed to act as protein anchors to orchestrate cell type-specific 3D genome architecture. MyoD is a pioneer TF for myogenic lineage specification. Here the authors provide further support for the role of MyoD in 3D genome architecture in muscle stem cells by comparing MyoD knockout and wild-type mice.
- Ruiting Wang
- , Fengling Chen
- & Dahai Zhu
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Article
| Open AccessLifelong single-cell profiling of cranial neural crest diversification in zebrafish
Cranial neural crest generates a wide diversity of cell types. Here the authors perform single-cell profiling of neural crest to identify key enhancers and transcription factors for cell fate competency, thus revealing progressive acquisition of fate potential.
- Peter Fabian
- , Kuo-Chang Tseng
- & J. Gage Crump
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Article
| Open AccessG-quadruplex DNA structures in human stem cells and differentiation
Whether G-quadruplexes (G4s) regulate stem cell self-renewal and fate determination during embryonic development is not well understood. Here, the authors reveal that the embryonic stem cell state is defined by very high G4 abundance. G4s are progressively lost during differentiation as cells transit to lower lineage potential while artificial G4 stabilisation leads to delayed differentiation.
- Katherine G. Zyner
- , Angela Simeone
- & Shankar Balasubramanian
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Article
| Open AccessLipid droplet availability affects neural stem/progenitor cell metabolism and proliferation
Lipid droplets (LDs) are central to lipid metabolism, which is known to regulate neural stem cell behavior. Here, the authors show that LDs influence neural stem cell proliferation and metabolic activity and change upon differentiation or quiescence.
- Mergim Ramosaj
- , Sofia Madsen
- & Marlen Knobloch
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