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| Open AccessProteins that bind regulatory regions identified by histone modification chromatin immunoprecipitations and mass spectrometry
The protein factors that bind to regulatory regions in the genome have not been systematically mapped. Here the authors performed chromatin immunoprecipitations for histone modifications associated with promoters, enhancers or heterochromatin in mouse embryonic stem cells and assigned a genome location to many factors important for pluripotency.
- Erik Engelen
- , Johannes H. Brandsma
- & Raymond A. Poot
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| Open AccessC8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling
Cancer stem cells are a small proportion of tumours that often confer resistance to chemotherapy but how these cells are maintained is unclear. Here, Zhu et al. study hepatocellular carcinoma stem cells and identify C8orf4 as a negative regulator of Notch2, which is required for the self-renewal of the cells.
- Pingping Zhu
- , Yanying Wang
- & Zusen Fan
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| Open AccessPDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium
Adult cardiac progenitor/stem cells (CPSCs) possess valuable potential for heart repair that is limited by the elusiveness of these cells. Here Noseda et al. refine the definition of murine CPSCs producing stem cell antigen 1 (Sca1), mapping the cardiogenic signature and clonogenicity to the subgroup of Sca1+cells expressing PDGFRα.
- Michela Noseda
- , Mutsuo Harada
- & Michael D. Schneider
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Muscle stem cells contribute to myofibres in sedentary adult mice
Skeletal muscle satellite cells are muscle stem cells believed to contribute only to regenerating myofibres. Here Keefe et al. show that in adult sedentary mice satellite cells continue to fuse with uninjured myofibres, but they are not globally required for the maintenance of aging muscles.
- Alexandra C. Keefe
- , Jennifer A. Lawson
- & Gabrielle Kardon
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| Open AccessReinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency
LIF/STAT3 signalling characterizes naive pluripotency in mouse embryonic stem cells (ESCs), but whether this pathway can sustain a similar state in human cells is not completely understood. Here the authors show that LIF stimulation and enhancement of STAT3 activity allow human ESCs to escape from FGF2 dependency and facilitates their entry into a naive-like state of pluripotency.
- Hongwei Chen
- , Irène Aksoy
- & Pierre Savatier
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| Open AccessNon-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells
The number of germline stem/progenitor cells in C. elegansdeclines with age. Here the authors show this cell loss is mediated by the transcription factor DAF-16/FOXO acting in specific somatic gonad cells, demonstrating that stem cell aging can be anatomically uncoupled from organismal aging.
- Zhao Qin
- & E. Jane Albert Hubbard
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Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways
Aging leads to impaired differentiation and increased pool size of hematopoietic stem cells (HSCs). Here, the authors show that wild-type p53-induced phosphatase 1 (Wip1), a negative regulator of DNA damage response pathways, regulates aging-associated HSC differentiation and expansion viap53 and mTORC1 pathways, respectively.
- Zhiyang Chen
- , Weiwei Yi
- & Zhenyu Ju
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Article
| Open AccessFoxp1-mediated programming of limb-innervating motor neurons from mouse and human embryonic stem cells
The differentiation of spinal motor neurons (MNs) from mouse and human embryonic stem cells provides opportunities to model MN development and disease, but most protocols produce only a subset of the MN subtypes found in vivo. Here the authors show that limb projecting lateral motor column MNs can be efficiently generated though the expression of Foxp1.
- Katrina L. Adams
- , David L. Rousso
- & Bennett G. Novitch
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G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy
In response to injury, satellite cells (SCs) asymmetrically divide to self-renew and repair muscle. Here the authors show that a cytokine G-CSF is crucial for long-term expansion of activated SCs and muscle regeneration in mice, suggesting that G-CSF treatment may have beneficial effect in Duchenne muscular dystrophy.
- Nozomi Hayashiji
- , Shinsuke Yuasa
- & Keiichi Fukuda
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Plasticity of Hopx+ type I alveolar cells to regenerate type II cells in the lung
Alveoli are the lung’s functional units composed of two major epithelial cell types, type I and type II. Type II cells are adult lung stem cells, but this study shows that differentiated Type I cells can also self-renew and give rise to Type II cells, revealing a bidirectional relationship between lung epithelial cell types.
- Rajan Jain
- , Christina E. Barkauskas
- & Jonathan A. Epstein
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Article
| Open AccessPontin functions as an essential coactivator for Oct4-dependent lincRNA expression in mouse embryonic stem cells
Long non-coding RNAs or lincRNAs identified in embryonic stem (ES) cells have been shown to regulate ES cell states; however, how these lincRNAs are regulated remains unclear. Here the authors show that the transcriptional coactivator Pontin regulates the expression of lincRNAs involved in ES cell maintenance in an Oct4-dependent manner.
- Kyungjin Boo
- , Jinhyuk Bhin
- & Sung Hee Baek
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Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle
The balancing apparatus of the inner ear relies on the mechanosensory activity of hair cells (HC), which are poorly regenerated upon loss in adult mammals. Here, the authors show that in newborn mice HC regenerate through proliferation and transdifferentiation of activated striolar supporting cells that express Lgr5.
- Tian Wang
- , Renjie Chai
- & Alan G. Cheng
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ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype
Basal-like breast cancer is a heterogeneous disease with poor prognosis; however, its cellular origins and aetiology are poorly understood. Here the authors provide evidence that ID4 is a key controller of mammary stem/progenitor cell self-renewal, acting upstream of Notch signalling to repress luminal fate commitment.
- Simon Junankar
- , Laura A. Baker
- & Alexander Swarbrick
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Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells
Applications of human pluripotent stem cells (hPSCs) for disease modelling or cell therapy are hindered by low efficiency and heterogeneity of target cell types differentiated from hPSCs, such as motor neurons (MNs). Here the authors develop a method to derive highly pure motor neuron progenitor populations from human embryonic and induced pluripotent stem cells that yield functional MNs.
- Zhong-Wei Du
- , Hong Chen
- & Su-Chun Zhang
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| Open AccessAnalysing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors
Profiling pluripotent stem cell (PSC)-derived neural progeny is of fundamental interest for characterizing stem cell differentiation. Here, the authors analyse neural progenitors consecutively derived from human PSCs, showing dynamic stage-specific transcriptional patterns for distinct neural progenitors.
- Reuven Edri
- , Yakey Yaffe
- & Yechiel Elkabetz
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HEB associates with PRC2 and SMAD2/3 to regulate developmental fates
In embryonic stem cells, extracellular signals are required to derepress developmental promoters to drive lineage specification, but the proteins involved in this process remain unknown. Here the authors show that the protein HEB directly associates with the Polycomb repressive complex 2 at genes involved in mesoderm and endoderm specification.
- Se-Jin Yoon
- , Joseph W. Foley
- & Julie C. Baker
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Article
| Open AccessPW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence
Mesoangioblasts are mesodermal stem cells with a therapeutic potential for treatment of muscular dystrophy due to their ability to differentiate into skeletal muscle. This study shows that the PW1/Peg3 protein is crucial for mesoangioblast myogenic and migratory potency and is a therapeutically relevant biomarker.
- Chiara Bonfanti
- , Giuliana Rossi
- & Graziella Messina
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The reverse evolution from multicellularity to unicellularity during carcinogenesis
Multicellularity relies on molecular mechanisms that promote cooperation of individual cells and limit their inappropriate expansion. Here Chen et al. show that genes unique to multicellular organisms are preferentially inactivated during tumour evolution.
- Han Chen
- , Fangqin Lin
- & Xionglei He
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Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue
The ciliary margin of the eye functions as a source of multipotent progenitor cells in certain organisms but whether it plays this role in humans has not been easy to study. Here the authors culture human embryonic stem cells that self-organize into retinal tissue, and show that ciliary margin-like growth zones emerge from the developing human retinal tissue and contain stem cell niches.
- Atsushi Kuwahara
- , Chikafumi Ozone
- & Yoshiki Sasai
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| Open AccessEpigenetic and transcriptional determinants of the human breast
Epigenetic changes associated with post-natal differentiation have been characterized. Here the authors generate epigenomic and transcriptional profiles from primary human breast cells, providing insights into the transcriptional and epigenetic events that define post-natal cell differentiation in vivo.
- Philippe Gascard
- , Misha Bilenky
- & Martin Hirst
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NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.
- Sung Jun Bae
- , Myungjin Kim
- & Jae Hong Seol
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Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells
Mice can be generated from induced pluripotent stem cells (iPSCs) but the impact of accumulated mutations on the developmental potential of the cells remains to be determined. Here the authors show that mice generated from iPSCs tolerate the accumulation of somatic mutations for up to six generations, but their viability decreased with increasing generations.
- Shuai Gao
- , Caihong Zheng
- & Shaorong Gao
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Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells
The cyclin-dependent kinase inhibitors p18 and p27 confer advantage to the propagation of haematopoietic stem cells (HSCs). In this manuscript, the authors demonstrate that p18 is a potent negative regulator of HSC self-renewal, and identify novel small molecules putatively inhibiting p18 that promote HSC growth in culture and mouse transplant assays.
- Yingdai Gao
- , Peng Yang
- & Xiang-Qun Xie
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Article
| Open AccessCollaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways
Improving the efficiency of reprogramming of somatic cells to induced pluripotent stem cells is of major interest. Here, the authors combine ascorbic acid and 2i (MAP kinase and GSK inhibitors) conditions and show increased efficiency and synchronicity in the reprogramming of fibroblasts and partially reprogrammed cells, and study epigenetic effectors and signalling pathways responsible for this effect.
- Khoa A. Tran
- , Steven A. Jackson
- & Rupa Sridharan
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NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes
Tumour cells disseminated from the primary tumour can remain dormant for years before initiating metastases. Here Sosa et al.show that the orphan nuclear receptor NR2F1 can be induced by bone marrow cues and by epigenetic drugs to promote quiescence and tumour cell dormancy in several cancer types.
- Maria Soledad Sosa
- , Falguni Parikh
- & Julio A. Aguirre-Ghiso
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Article
| Open AccessROW1 maintains quiescent centre identity by confining WOX5 expression to specific cells
The quiescent centre controls stem cell differentiation at the root apical meristem. Here Zhang et al. propose that ROW1 maintains meristem cell identity by repressing expression of the WOX5transcription factor in the proximal meristem zone, thus confining its activity to the quiescent centre.
- Yuzhou Zhang
- , Yue Jiao
- & Yu-Xian Zhu
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Article
| Open AccessDppa3 expression is critical for generation of fully reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting
Reprogramming of mouse somatic cells into iPSCs often generates pre-iPSCs, low-grade iPSCs that show abnormal Dlk1-Dio3 imprinting, and fully reprogrammed, high-grade iPSCs. Here, the authors show that germ-cell marker Dppa3 enhances reprogramming kinetics, critical for the maintenance of Dlk1-Dio3 imprinting and generation of fully reprogrammed iPSCs.
- Xingbo Xu
- , Lukasz Smorag
- & D. V. Krishna Pantakani
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| Open AccessInterfering with stem cell-specific gatekeeper functions controls tumour initiation and malignant progression of skin tumours
The presence of multiple stem and progenitor cells in the skin has a major impact on the formation of different epidermal tumours. Here the authors identify bulge stem cells as the cells of origin of sebaceous tumours through genetic lineage tracing and molecular studies in a mouse model.
- Monika Petersson
- , Karen Reuter
- & Catherin Niemann
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Article
| Open AccessHuman iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects spinal cord motor neurons. Here the authors use induced pluripotent stem cell-derived motor neurons obtained from patients with ALS-linked mutations, and find functional deficits resulting from a progressive decrease in voltage-activated Na+ and K+currents that occur in the absence of cell death.
- Anna-Claire Devlin
- , Karen Burr
- & Gareth B. Miles
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Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT2R and cytoskeletal dysregulation
Increased levels of haematopoietic stem and progenitor cells in the blood have been linked to some forms of organ failure. Here, the authors show that the hormone angiotensin II increases mobilization of haematopoietic stem and progenitor cells by inducing cytoskeletal changes in bone marrow cells.
- Kyung Hee Chang
- , Ramesh C Nayak
- & Jose A Cancelas
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| 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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Small RNA changes en route to distinct cellular states of induced pluripotency
Somatic cell reprogramming can induce distinct pluripotent states. Here the authors perform time-resolved small RNA expression profiling during the reprogramming of mouse embryonic fibroblasts and observe that distinct miRNA milieus characterise alternate states of pluripotency.
- Jennifer L. Clancy
- , Hardip R. Patel
- & Thomas Preiss
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Proteome adaptation in cell reprogramming proceeds via distinct transcriptional networks
During somatic cell reprogramming, the cell transits through intermediate states. Here, the authors perform an in-depth quantitative proteomic analysis of the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells and observe two waves of proteome reorganisation.
- Marco Benevento
- , Peter D. Tonge
- & Albert J. R. Heck
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| Open AccessAn epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator
Somatic cell reprogramming can induce distinct pluripotent states. Here the authors perform time-resolved whole-genome bisulfite sequencing during the reprogramming of mouse embryonic fibroblasts and report dynamic global DNA methylation changes.
- Dong-Sung Lee
- , Jong-Yeon Shin
- & Jeong-Sun Seo
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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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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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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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Article
| Open AccessTargeted and genome-wide sequencing reveal single nucleotide variations impacting specificity of Cas9 in human stem cells
The microbial RNA-guided CRISPR/Cas9 system has robust genome-editing activities, but the off-target effects of the Cas9 nuclease have only recently begun to be analysed. Here the authors provide evidence for high specificity of the Cas9 nuclease on targeting of the Tafazzin gene in human-induced pluripotent stem cells and demonstrate the impact of single-nucleotide variations of the human genome on Cas9 specificity.
- Luhan Yang
- , Dennis Grishin
- & George Church
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Article
| 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 AccessCpG island-mediated global gene regulatory modes in mouse embryonic stem cells
CpG islands are high GC content DNA elements that surround the majority of transcriptional start sites in eukaryotes. Here, the authors analyse over 200 genomic data sets to provide new insight into global CpG islands-dependent regulatory mechanisms in differentiated and pluripotent stem cells.
- Samuel Beck
- , Bum-Kyu Lee
- & Jonghwan Kim
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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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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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Article
| Open AccessRole of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells
Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.
- Chen Chen
- , Peng Jiang
- & Wenbin Deng
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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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Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs
Fanconi anaemia (FA) is a genetic disease associated with low levels of blood stem cells. Here Liu et al.report an improved method to generate genetically corrected induced pluripotent stem cells from an FA patient, and perform a screening to identify drugs that improve their differentiation into blood stem cells.
- Guang-Hui Liu
- , Keiichiro Suzuki
- & Juan Carlos Izpisua Belmonte
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Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations
De novocopy number variations are known to occur in somatic cell populations and pluripotent stem cells. Here the authors use single-cell array comparative genomic hybridization to identify copy number variations in individual human somatic and embryonic stem cells.
- Kurt Jacobs
- , Afroditi Mertzanidou
- & Claudia Spits
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Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration
The age-related decline in the regenerative capacity of muscle can be reversed in mice by exposure to young circulation. Elabd et al.identify the hormone, oxytocin, as a potential mediator of this effect, showing that its plasma levels decline with age and that administration of oxytocin to aged mice improves muscle regeneration.
- Christian Elabd
- , Wendy Cousin
- & Irina M. Conboy
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Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs
Induced pluripotent stem cells (iPSCs) hold great potential for modelling human developmental processes and diseases. Here the authors induce human iPSCs to spontaneously form fully laminated three-dimensional retinal tissue containing functional photoreceptor cells.
- Xiufeng Zhong
- , Christian Gutierrez
- & M. Valeria Canto-Soler
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