Featured
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Article
| Open AccessDefining stem cell dynamics and migration during wound healing in mouse skin epidermis
Wound healing is essential to repair the skin after injury and distinct stem cells in the epidermis are known to contribute to the process. Here the authors perform molecular, functional and clonal analysis and reveal the individual contribution of stem cells coming from different epidermal compartments to the wound-healing process in mice.
- Mariaceleste Aragona
- , Sophie Dekoninck
- & Cédric Blanpain
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Article
| Open AccessHierarchical tissue organization as a general mechanism to limit the accumulation of somatic mutations
To limit the accumulation of somatic mutations, renewing tissues must minimize the number of times each cell divides during differentiation. Here, the authors analytically derive the lower limit of lifetime divisional load of a tissue, show that hierarchically differentiating tissues can approach this limit, and that this depends on uneven divisional rates across the hierarchy.
- Imre Derényi
- & Gergely J. Szöllősi
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Article
| Open AccessClonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate
Age-associated decline in tissue function has been linked to alterations in adult stem cells, with implications for organ homeostasis and cellular therapy. Here, the authors study the heterogeneity of ageing mouse haematopoietic stem cells (HSCs) and find that the compromised blood cell-forming potential of individual and functionally defined aged HSCs can be reset by reprogramming.
- Martin Wahlestedt
- , Eva Erlandsson
- & David Bryder
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Article
| Open AccessInduced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours
Several breast cancers may originate from mammary luminal cells and inactivating mutations of p53 are present in most triple-negative breast cancers. Here, the authors show that loss of p53 from luminal cells in mice results in their clonal expansion and mammary tumour formation.
- Luwei Tao
- , Dongxi Xiang
- & Zhe Li
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Article
| Open AccessStepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2
Liver and pancreas cells arise from a common endoderm progenitor in the embryo, but what regulates their cell fate is unclear. Here, the authors show that expression of the Three-Amino-acid-Loop-Extension (TALE) homeobox TG-interacting factor 2 (TGIF2) in hepatocytes reprogrammes the cells to a pancreatic fate.
- Nuria Cerdá-Esteban
- , Heike Naumann
- & Francesca M. Spagnoli
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Article
| Open Accessp190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation
The success of hematopoietic stem cell (HSC) transplantation relies on understanding what regulates the fate decision to self-renew. Here, the authors show using bothin vitro assays and in vivotransplantation that loss of the RhoGAP p190-B enhances self-renewal by inhibiting TGFβ/p38 signalling.
- Ashwini Hinge
- , Juying Xu
- & Marie-Dominique Filippi
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Article
| Open AccessTwo factor-based reprogramming of rodent and human fibroblasts into Schwann cells
Schwann cells (SCs) myelinate peripheral nerve axons and offer opportunities for the treatment of injuries and demyelinating diseases but reliable and renewable sources of these cells are hard to come by. Here the authors reprogram rat, mouse and human fibroblasts into Schwann cells using two transcription factors.
- Pietro Giuseppe Mazzara
- , Luca Massimino
- & Vania Broccoli
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Article
| Open AccessA Lin28 homologue reprograms differentiated cells to stem cells in the moss Physcomitrella patens
Land plants and metazoans are both able to reprogram differentiated cells to stem cells under certain circumstances. Here the authors show that the moss CSP1 protein, which shares conserved domains with the mammalian pluripotent stem cell factor Lin28, promotes reprogramming of leaf cells to apical stem cells.
- Chen Li
- , Yusuke Sako
- & Mitsuyasu Hasebe
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Article
| Open AccessMicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes
MicroRNAs have important roles in regulating tumor development, progression and metastasis. Here, the authors demonstrate the tumor-suppressive functions of miRNA141 in prostate cancer stem cells mediated by directly targeting CD44, Rho GTPase protein family members, and EZH2.
- Can Liu
- , Ruifang Liu
- & Dean G. Tang
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Article
| Open AccessDissecting cell-type-specific roles of androgen receptor in prostate homeostasis and regeneration through lineage tracing
Androgen receptor is an important regulator of prostate development and cancer. In this study, the authors use genetic lineage tracing in mice to clarify the role of AR in different prostate epithelial cells.
- Qing Xie
- , Yueli Liu
- & Zhu A. Wang
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Article
| Open AccessThe impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells
MicroRNAs can posttranscriptionally repress multiple targets in a cell population. Here the authors use single-cell sequencing to investigate the effects of an individual miRNA on transcriptional heterogeneity and gene co-expression
- Gennaro Gambardella
- , Annamaria Carissimo
- & Robert Blelloch
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Article
| Open AccessWhole-brain 3D mapping of human neural transplant innervation
Transplantation of cells into the central nervous system has developed into a major avenue for replacing neurons lost to neurodegenerative disease. Here the authors develop an approach combining viral-based transynaptic tracing labeling and whole brain imaging to trace synaptic innervation of human neurons transplanted into a mouse background.
- Jonas Doerr
- , Martin Karl Schwarz
- & Oliver Brüstle
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Article
| Open AccessPten is necessary for the quiescence and maintenance of adult muscle stem cells
Pten is known to regulate haematopoietic stem cell functions. Here the authors show that Ptenalteration of Notch signalling has stage-specific muscle regenerative functions in muscle stem cells by preventing premature differentiation of quiescent cells and enhancing the self-renewal of activated cells.
- Feng Yue
- , Pengpeng Bi
- & Shihuan Kuang
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Article
| Open AccessBi- and uniciliated ependymal cells define continuous floor-plate-derived tanycytic territories
Ependymal cells lining the adult brain ventricles are comprised of multiciliated cells and a rare subpopulation with two cilia (E2 cells) whose origin and function remain unknown. Here the authors find E2 cells in the 3rd ventricle of mice and humans, along with a third ependymal cell type with only a primary cilium, and provide details of their marker profile and developmental origins.
- Zaman Mirzadeh
- , Yael Kusne
- & Arturo Alvarez-Buylla
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Article
| Open AccessPraja1 E3 ubiquitin ligase promotes skeletal myogenesis through degradation of EZH2 upon p38α activation
In skeletal muscle progenitors, EZH2 maintains myogenic genes in a repressed state, but during differentiation its levels are reduced via unknown mechanisms. Here the authors show that during myogenesis, p38α kinase phosphorylates EZH2 and targets it for degradation by the ubiquitin ligase PRAJA1.
- Silvia Consalvi
- , Arianna Brancaccio
- & Daniela Palacios
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Article
| Open AccessBMP restricts stemness of intestinal Lgr5+ stem cells by directly suppressing their signature genes
Bone morphogenetic protein (BMP) maintains intestinal homeostasis by restricting its hyperproliferation but whether it directly regulates the stem cells is unknown. Here the authors show that BMP constrains the Lgr5+stem cell expansion under both homeostatic and injury conditions through Smad-mediated repression of stem cell signature genes.
- Zhen Qi
- , Yehua Li
- & Ye-Guang Chen
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Article
| Open AccessTherapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome
Stem cells exert their beneficial effects through secretion of regenerative factors. Here, the authors take the membranes and secreted factors from cardiac stem cells and generate a synthetic cell-mimicking microparticle, which, on injection in a mouse model of myocardial infarction, improves cardiac function.
- Junnan Tang
- , Deliang Shen
- & Ke Cheng
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Article
| Open AccessEndothelial-specific inhibition of NF-κB enhances functional haematopoiesis
The complex microenvironmental signalling pathways that govern haematopoietic stem cell (HSC) activity remain poorly defined. Here, the authors identify endothelial NF-κB signalling as regulating regenerative HSC function, accelerating haematopoietic recovery following myelosuppressive injury in mice.
- Michael G. Poulos
- , Pradeep Ramalingam
- & Jason M. Butler
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Article
| Open AccessBulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells
Differentiation of human pluripotent stem cells (hPSC) mimics aspects of embryonic developmentin vitrobut is poorly understood. Here, the authors identify bulk cell density as a key parameter directing transition from pluripotency to primitive streak-like priming in hPSCs via secreted LEFTY/CERBERUS.
- Henning Kempf
- , Ruth Olmer
- & Robert Zweigerdt
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Article
| Open AccessChromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish
The adult zebrafish heart is capable of regeneration but the molecular mechanisms are poorly understood. Here the authors show that chromatin remodeling factor Brg1 represses cyclin-dependent kinase inhibitors to promote myocardial regeneration.
- Chenglu Xiao
- , Lu Gao
- & Jing-Wei Xiong
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Article
| Open AccessThioredoxin-interacting protein regulates haematopoietic stem cell ageing and rejuvenation by inhibiting p38 kinase activity
The processes regulating the ageing of stem cells are not clearly defined. Here, the authors report that in haematopoietic stem cells (HSC) thioredoxin-interacting protein, known to regulate the cell cycle, binds to p38 mitogen-activated protein kinase and regulates HSC ageing and rejuvenation.
- Haiyoung Jung
- , Dong Oh Kim
- & Inpyo Choi
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Article
| Open AccessOutside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis
Integrins regulate haematopoietic stem cell (HSC) homeostasis and engraftment into the bone marrow (BM) niche upon transplantation. Here, the authors show that HSC quiescence and function in the BM is regulated by the interaction of PERIOSTIN and INTEGRIN αv and subsequent increase in p27Kip1.
- Satish Khurana
- , Sarah Schouteden
- & Catherine M. Verfaillie
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Article
| Open AccessTransplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion
Previous studies have used fluorescently labelled cells to demonstrate the incorporation of transplanted photoreceptor precursors into the mouse retina. Here, the authors show that fluorescent proteins are passed between the host and transplanted cells rather than migration of donor cells into the retina.
- Mandeep S. Singh
- , Jasmin Balmer
- & Robert E. MacLaren
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Article
| Open AccessSomatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan
Pluripotent stem cells are thought to require a highly active proteostatic machinery. Here, the authors show that CCT8, a subunit of the proteostatic chaperonin complex, is increased in pluripotent stem cells, and that overexpression of CCT8 in worms increases cellular proteostasis and organismal longevity.
- Alireza Noormohammadi
- , Amirabbas Khodakarami
- & David Vilchez
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Article
| Open AccessThe deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog
Nanog regulates embryonic stem cell (ESC) pluripotency but what controls Nanog protein stability is unclear. Here, the authors show that in mouse ESCs, Nanog protein is ubiquitinated and stabilized by the deubiquitinase USP21, which in turn is regulated by extrinsic signals, STAT3 and ERK.
- Jiali Jin
- , Jian Liu
- & Ping Wang
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Article
| Open AccessReprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors
Direct reprogramming of closely-related lineages can generate hematopoietic stem cells. Here, the authors show hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can reprogram fibroblasts into induced hematopoietic progenitors (iHPs), which are engraftable blood progenitors.
- Hui Cheng
- , Heather Yin-Kuan Ang
- & Bing Lim
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Article
| Open AccessLack of Diaph3 relaxes the spindle checkpoint causing the loss of neural progenitors
Molecular mechanisms that control the division of neural progenitor cells are only partially understood. Here the authors show that Diaph3 is critical for spindle checkpoint activity in cortical progenitor cells as the loss of Diaph3 leads to apoptosis of progenitor cells and eventually results in microcephaly in mice.
- Devid Damiani
- , André M. Goffinet
- & Fadel Tissir
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Article
| Open AccessREST regulation of gene networks in adult neural stem cells
The transcription factor REST plays a crucial role in maintaining the adult neural stem cell pool. To better understand how REST maintains quiescence in neural progenitors, the authors use ChIP-seq and RNA-seq and find that REST regulates represses ribosome biogenesis, cell cycle and neuronal genes.
- Shradha Mukherjee
- , Rebecca Brulet
- & Jenny Hsieh
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Article
| Open AccessLong non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling
Long non-coding RNAs (lncRNA) are known to regulate human embryonic stem cell (hESC) self-renewal. Here, the authors identify lncRNA growth-arrest-specific transcript 5 (GAS5) that regulates pluripotency via modulation of NODAL signalling to maintain self-renewal in hESCs.
- Chen Xu
- , Yan Zhang
- & Houqi Liu
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Article
| Open AccessTetrapod limb and sarcopterygian fin regeneration share a core genetic programme
Salamanders are unique among extant tetrapods for their ability to completely regenerate their limbs. Here, Nogueira and colleagues show that lungfishes, the sister clade of tetrapods, regenerate their fins using analogous gene regulatory changes and morphological steps.
- Acacio F. Nogueira
- , Carinne M. Costa
- & Igor Schneider
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Article
| Open AccessBioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction
Stem cell therapy of myocardial infarction is hampered by poor survival of injected cells. Here the authors develop injectable aggregates of stem cells differentiated to an early cardiac stage and encapsulated in a biodegradable micromatrix, and show their enhanced therapeutic efficacy in a heart infarction mouse model.
- Shuting Zhao
- , Zhaobin Xu
- & Xiaoming He
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Article
| Open AccessMitochondrial function controls intestinal epithelial stemness and proliferation
It is unclear what role mitochondrial function plays in maintaining intestinal epithelial cell (IEC) homeostasis. Here, the authors deplete a mitochondrial chaperone, heat shock protein 60 (HSP60) in IEC and observe a loss of stemness and cell proliferation, and suggest this is accompanied by a compensatory release of WNT-related factors.
- Emanuel Berger
- , Eva Rath
- & Dirk Haller
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Article
| Open AccessWnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids
Three-dimensional culture systems and organoids for mammary glands are important to understand mammary gland development. Here, the authors identify conditions (including Neuregulin 1 and R-spondin 1) that allow the culture of organoids that are responsive to hormonal stimulation for up to 2.5 months.
- Thierry Jardé
- , Bethan Lloyd-Lewis
- & Trevor C. Dale
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Article
| Open AccessSingle-cell lineage tracing in the mammary gland reveals stochastic clonal dispersion of stem/progenitor cell progeny
The identity and origin of adult mammary stem cells has been much debated. Here, the authors use a stochastic genetic labelling approach, together with optical tissue clearing, to visualize clonal progeny and show that unipotent stem/progenitor cells contribute to adult mammary gland development.
- Felicity M. Davis
- , Bethan Lloyd-Lewis
- & Christine J. Watson
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Article
| Open AccessSemi-automated closed system manufacturing of lentivirus gene-modified haematopoietic stem cells for gene therapy
Current methods for haematopoietic stem cell gene therapy are laborious and require special licensed facilities. Here the authors develop a semi-automated protocol using a commercially available device to allow for benchtop generation of gene-modified blood cell products for transplantation, that meet current standards.
- Jennifer E. Adair
- , Timothy Waters
- & Hans-Peter Kiem
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Article
| Open AccessPurification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1
Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker, LRTM1, to enrich the midbrain dopaminergic progenitors and show improved motor function/cell survival when grafted into rat/monkey brains, respectively.
- Bumpei Samata
- , Daisuke Doi
- & Jun Takahashi
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Article
| Open AccessMacrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury
The intestinal stroma secretes WNT ligands but the role of WNT in intestinal repair is unclear. Here, the authors show that when WNT synthesis is ablated from stromal macrophages, the intestine morphology is normal but hypersensitive to radiation injury, implicating macrophage-derived WNT in intestinal repair.
- Subhrajit Saha
- , Evelyn Aranda
- & Jeffrey W. Pollard
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Article
| Open AccessSpecification of haematopoietic stem cell fate via modulation of mitochondrial activity
Haematopoietic stem cells rely on glycolysis for their energy demands but whether this affects their fate is unknown. Here, the authors show that forcing the cells to rely on glycolysis is important for self-renewal and that this involves a reduction in mitochondrial mass.
- Nicola Vannini
- , Mukul Girotra
- & Matthias P. Lutolf
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Article
| Open AccessThe transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation
Skeletal muscle has remarkable adaptive and regenerative capacity. Here the authors show that the transcription factor Prox1 is necessary for maintenance of slow muscle fibre types via activation of NFAT signalling, and for myoblast differentiation via cross-talk with the Notch signalling pathway.
- Riikka Kivelä
- , Ida Salmela
- & Kari Alitalo
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Article
| Open AccessIdentification of a common mesenchymal stromal progenitor for the adult haematopoietic niche
How the environment of the niche regulates haematopoietic stem cells (HSC) is unclear. Here, the authors identify a mesenchymal stromal progenitor hierarchy and identify Sca1+ cells as common progenitors for mesenchymal stromal cells in the adult niche that provide a supportive environment for hematopoiesis.
- Xingbin Hu
- , Mayra Garcia
- & Ching-Cheng Chen
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Article
| Open AccessExploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury
A potentially superior tissue regenerative strategy to stem cell transplantation is modulation of endogenous stem cells. Here the authors show fibrocartilage stem cells exist in the temporomandibular joint that contribute to cartilage regeneration and can be manipulated to enhance regeneration through canonical Wnt signalling.
- Mildred C. Embree
- , Mo Chen
- & Jeremy J. Mao
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Article
| Open AccessRetinal transplantation of photoreceptors results in donor–host cytoplasmic exchange
Integration of transplanted photoreceptors into the host retina has been assumed as the underlying mechanism for vision improvement in pre-clinical studies. Here, the authors show that the majority of transplanted photoreceptors do not structurally integrate but exchange intercellular material with host cells.
- Tiago Santos-Ferreira
- , Sílvia Llonch
- & Marius Ader
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Article
| Open AccessDonor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors
Transplantation of healthy photoreceptor cells has been shown to rescue blindness. Here, the authors show that rather than donor cells integrating into the host retina, the predominant mechanism underlying this rescue involves exchange of cytoplasmic material between donor and host cells in vivo.
- R. A. Pearson
- , A. Gonzalez-Cordero
- & R. R. Ali
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Article
| Open AccessMice produced by mitotic reprogramming of sperm injected into haploid parthenogenotes
It is unclear what regulates gamete reprogramming competence. Here, the authors inject sperm into parthenogenetic embryos, generating viable offspring and show that mouse embryos in the mitotic cell cycle can reprogram sperm for full term development.
- Toru Suzuki
- , Maki Asami
- & Anthony C. F. Perry
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Article
| Open AccessLECT2 drives haematopoietic stem cell expansion and mobilization via regulating the macrophages and osteolineage cells
How extramedullar cytokines regulate hematopoietic stem cell (HSC) homeostasis is unclear. Here, the authors show that the cytokine leukocyte cell-derived chemotaxin 2 regulates HSC expansion and mobilisation via tumour necrosis factor and interaction with CD209a in macrophages.
- Xin-Jiang Lu
- , Qiang Chen
- & Jiong Chen
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Article
| Open AccessCripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency
Stem cell plasticity is crucial for early embryo development and the differentiation of stem cells. Here, the authors show that the extracellular protein Cripto sustains mouse ESC self-renewal and maintains mouse EpiSC as well as human ESC pluripotency and controls the metabolic reprogramming in ESCs to EpiSC transition.
- Alessandro Fiorenzano
- , Emilia Pascale
- & Gabriella Minchiotti
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Article
| Open AccessNestin+ cells direct inflammatory cell migration in atherosclerosis
Bone marrow cells producing the intermediate filament nestin guide monocyte egress to the bloodstream in response to infection. Here, the authors show that nestin-producing stromal cells direct inflammatory cell migration in atherosclerosis, and that stromal Mcp1 is crucial in this process.
- Raquel del Toro
- , Raphael Chèvre
- & Simón Méndez-Ferrer
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Article
| Open AccessTNIK inhibition abrogates colorectal cancer stemness
TRAF2 and NCK-interacting protein kinase (TNIK) is a key regulatory component of the TCF4 and β-catenin transcriptional complex. In this study, the authors identify a TNIK inhibitor that blocks Wnt signalling and Wnt-driven colorectal tumorigenesis in mice.
- Mari Masuda
- , Yuko Uno
- & Tesshi Yamada
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Article
| Open AccessLncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression
Liver tumour-initiating cells (TICs) may be responsible for liver cancer initiation and recurrence. In this article, the authors show that a previously unidentified lncRNA, LncSox4, is highly expressed in liver cancer TICs and regulates TIC self-renewal through the Stat3/SOX4 axis.
- Zhen-zhen Chen
- , Lan Huang
- & Yan-feng Gao
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