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Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells
The hair follicle bulge contains epithelial stem cells that contribute to follicle formation during each hair cycle. Here the authors differentiate human induced pluripotent stem cells into folliculogenic epithelial stem cells, which can produce all hair follicle lineages including a stem cell population.
- Ruifeng Yang
- , Ying Zheng
- & Xiaowei Xu
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| Open AccessClonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment
Laminin-511 and its cell-binding domain support long-term self-renewal of human pluripotent stem cells in xeno-free culture conditions. Here the authors show that a xeno-free culture matrix consisting of a full-length laminin-521 and the cell–cell adhesion protein E-cadherin supports clonal expansion of human embryonic stem cells.
- Sergey Rodin
- , Liselotte Antonsson
- & Karl Tryggvason
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Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells
The histone demethylase Lsd1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Here, the authors show that the loss of Lsd1 in the trophectoderm of mouse embryos leads to premature differentiation of trophoblast stem cells, partially due to de-repression of the transcription factor Ovol2.
- Dongmei Zhu
- , Stefanie Hölz
- & Roland Schüle
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| Open AccessA paracrine network regulates the cross-talk between human lung stem cells and the stroma
The human lung contains Lgr6-positive progenitor cells, which have the potential to generate multiple epithelial lineages in cell explant studies. Here, the authors present a role of p38a MAPK signalling in regulating the cross-talk between this lung progenitor cell population and the stromal and endothelial cells comprising their niche microenvironment.
- E. Josue Ruiz
- , Feride Oeztuerk-Winder
- & Juan-Jose Ventura
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Snail1-dependent control of embryonic stem cell pluripotency and lineage commitment
Factors inducing epithelial to mesenchymal transition, such as the transcriptional repressor Snail1, have been implicated in cancer stem cell development and function. Here Lin et al.report that endogenous Snail1 is not required for embryonic stem cell pluripotency and self-renewal, but rather regulates Wnt-induced epiblast differentiation.
- Yongshun Lin
- , Xiao-Yan Li
- & Stephen J. Weiss
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Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level
Haematopoietic stem cells emerge from the haemogenic endothelium via an endothelial-to-haematopoietic transition. Here, the authors show using single cell functional and transcriptional analyses that haemogenic endothelial cells begin to lose their endothelial potential while still located within the haemogenic endothelium.
- Gemma Swiers
- , Claudia Baumann
- & Marella F. T. R. de Bruijn
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Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology
Myofibroblasts drive fibrogenesis in the liver but their cellular origins remain unclear. Here Mederacke et al. use the Lratgene to label hepatic stellate cells (HSCs) in transgenic mice and reveal HSCs as the major source of myofibroblasts in models of toxic, biliary and fatty liver fibrosis.
- Ingmar Mederacke
- , Christine C. Hsu
- & Robert F. Schwabe
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iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF
The neurotrophic cytokine leukaemia inhibitory factor (LIF) prevents oligodendrocyte death in animal models of multiple sclerosis. Here, Laterza et al. show that secretion of LIF from transplanted iPSC-derived neural progenitor cells has a therapeutic effect in a mouse model of multiple sclerosis.
- Cecilia Laterza
- , Arianna Merlini
- & Gianvito Martino
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Gene regulation and priming by topoisomerase IIα in embryonic stem cells
Topoisomerase 2α (Top2α) has essential roles during DNA replication, whereas its isoform Top2β is implicated in gene expression. Thakurela et al.show that Top2α is also required for stem-cell transcriptome regulation and primes developmental genes for activation by Top2β upon terminal differentiation.
- Sudhir Thakurela
- , Angela Garding
- & Vijay K. Tiwari
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MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation
MBNL and FOX splicing factors are known to have a role in the differentiation of muscle and the nervous system during development. In this study, the authors show that MBNL1 and RBFOX2 regulate alternative splicing of genes that are required specifically for late mesoderm differentiation.
- Julian P. Venables
- , Laure Lapasset
- & Jamal Tazi
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Modulation of β-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal
Wnt/β-catenin signalling can regulate both self-renewal and differentiation of pluripotent stem cells. Here Kim et al.show that transcriptional regulation by nuclear β-catenin induces the differentiation of mouse epiblast stem cells and human embryonic stem cells, whereas cytoplasmic β-catenin supports their self-renewal.
- Hoon Kim
- , Jun Wu
- & Qi-Long Ying
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| Open AccessComplement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration
Components of the complement system have been shown to promote liver regeneration. Haynes et al. demonstrate that the complement fragment C3a can induce regeneration of the embryonic chick retina from stem and progenitor cells of the ciliary margin via activation of STAT3 and other downstream signalling pathways.
- Tracy Haynes
- , Agustin Luz-Madrigal
- & Katia Del Rio-Tsonis
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Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells
Artificial heart tissue may find application in novel therapies of cardiac disease in the future. Here, Lu et al. take a step towards the creation of personalized heart tissue by repopulating decellularized mouse hearts with cells derived from human induced pluripotent stem cells.
- Tung-Ying Lu
- , Bo Lin
- & Lei Yang
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| Open AccesshESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury
Astroglia are heterogeneous in phenotype and not all astrocytes are equivalent in their ability to repair injured brain. Here, the authors show that two defined subtypes of astroglia generated from hESC-derived Olig2-positive versus Olig2-negative neural progenitors, exhibit distinct properties and neuroprotective effects.
- Peng Jiang
- , Chen Chen
- & Wenbin Deng
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The p53–PUMA axis suppresses iPSC generation
Inhibition of the p53–p21 axis increases reprogramming efficiency of somatic cells into induced pluripotent stem cells (iPSCs). Here the authors show that depletion of the pro-apoptotic factor PUMA, acting downstream of p53, increases reprogramming efficiency, providing new insights into the roles of p53 in reprogramming.
- Yanxin Li
- , Haizhong Feng
- & Tao Cheng
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| Open Accessα-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors
De novoneurogenesis occurs within the adult hypothalamus, suggesting the existence of a local neural stem cell niche. Here, the authors show that α-tanycytes lining the third ventricle are self-renewing multipotent neural stem cells, whose proliferation is dependent upon local FGF signalling.
- S.C. Robins
- , I. Stewart
- & M. Placzek
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Immunologic and chemical targeting of the tight-junction protein Claudin-6 eliminates tumorigenic human pluripotent stem cells
The potential tumorigenicity of human pluripotent stem cells (hPSCs) limits their application in cell therapies. Ben-David et al.identify the tight-junction protein Claudin-6 as a cell-surface marker of hPSCs, and demonstrate three Claudin-6-based strategies to remove tumorigenic hPSCs from mixed cell cultures.
- Uri Ben-David
- , Neta Nudel
- & Nissim Benvenisty
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Collagen VI regulates satellite cell self-renewal and muscle regeneration
Satellite cells have important roles in homeostasis and regeneration of skeletal muscles. Urciuolo et al. show that the extracellular matrix protein collagen VI is required for preserving satellite cell self-renewal and muscle regeneration in vitro and in vivoby modulating muscle mechanical properties.
- Anna Urciuolo
- , Marco Quarta
- & Paolo Bonaldo
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Zscan4 restores the developmental potency of embryonic stem cells
Mouse embryonic stem cells gradually lose their developmental potency in long-term culture. Here the authors show that their deteriorating developmental potency can be restored by transient activation of the Zscan4gene.
- Tomokazu Amano
- , Tetsuya Hirata
- & Minoru S. H. Ko
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TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells
TRF-1 is a telomere-binding protein that protects chromosome ends from degradation. Schneider and colleagues show that TRF1 is a marker of adult stem cell compartments and of induced pluripotent stem cells, and that TRF1 is essential for the induction and maintenance of pluripotency.
- Ralph P. Schneider
- , Ianire Garrobo
- & Maria A. Blasco
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| Open AccessDll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis
Neural stem cells in the adult brain maintain their pool size while producing new neurons. Kawaguchi et al.show that, during neural stem cell mitosis in the adult mouse subventricular zone, the Notch ligand Dll1 is asymmetrically segregated to one daughter cell, which undergoes differentiation.
- Daichi Kawaguchi
- , Shohei Furutachi
- & Yukiko Gotoh
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| Open AccessPAD4 regulates proliferation of multipotent haematopoietic cells by controlling c-myc expression
Histone citrullination by peptidylarginine deiminase 4 (PAD4) regulates transcription but its physiological role is unclear. Here Nakashima et al. show that PAD4 controls proliferation of multipotent haematopoietic cells by modulating c-myc expression.
- Katsuhiko Nakashima
- , Satoko Arai
- & Toru Miyazaki
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Max is a repressor of germ cell-related gene expression in mouse embryonic stem cells
Even though both embryonic stem cells and primordial germ cells express pluripotency markers, they differ in their developmental potential. Maeda et al. show that, in embryonic stem cells, the Myc family member Max mediates epigenetic repression of genes involved in germ cell development.
- Ikuma Maeda
- , Daiji Okamura
- & Yasuhisa Matsui
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Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81
The skeletal muscle has a remarkable capacity to regenerate after injury. Here Charrin et al. reveal that restoration of muscle architecture after injury requires a tight control of muscle cell fusion by the tetraspanin proteins CD9 and CD81 through their interaction with the cell surface protein CD9P-1.
- Stéphanie Charrin
- , Mathilde Latil
- & Eric Rubinstein
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Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking
Klf5 is a transcription factor that regulates self-renewal of pluripotent stem cells. Here the authors test the function of Klf5 in somatic stem cells, and discover that it controls stem cell homing and adhesion by regulating endocytosis of beta integrins.
- E. Taniguchi Ishikawa
- , K. H. Chang
- & J. A. Cancelas
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MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency
Chromatin templates can act as barriers against cellular reprogramming. Gaspar-Maia and colleagues use mouse models deficient in the histone variants macroH2A1 and macroH2A2, and find that macroH2A functions as an epigenetic barrier against induced pluripotency by silencing Utx target genes.
- Alexandre Gaspar-Maia
- , Zulekha A. Qadeer
- & Emily Bernstein
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Haematopoietic cells produce BDNF and regulate appetite upon migration to the hypothalamus
Brain-derived neurotrophic factor is produced in the brain and is a known regulator of energy homoeostasis. Here Urabe and colleagues show that brain-derived neurotrophic factor-producing haematopoietic cells control appetite by migrating into the hypothalamus, where they make contact with neurons.
- Hiroshi Urabe
- , Hideto Kojima
- & Hiroshi Kimura
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Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells
Stem cells have raised hopes of developing regenerative therapies of renal disease. Here, Osafune et al.provide a protocol for the differentiation of induced human pluripotent stem cells into renal lineages with the capacity to form tubular renal structures in mice.
- Shin-Ichi Mae
- , Akemi Shono
- & Kenji Osafune
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Analysis of protein-coding mutations in hiPSCs and their possible role during somatic cell reprogramming
Recent studies have shown that human induced pluripotent stem cells contain point mutations in coding regions, but the functional significance of these mutations is unclear. Here the authors provide evidence that these mutations are unlikely to confer a selective advantage for reprogramming.
- Sergio Ruiz
- , Athurva Gore
- & Juan Carlos Izpisua Belmonte
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| Open AccessA thermoresponsive and chemically defined hydrogel for long-term culture of human embryonic stem cells
To transfer cultured human embryonic stem cells (hESCs) between culture dishes, cells need to be released using mechanical, enzymatic or chemical means, which can damage cells. Zhanget al. describe a thermomodulatable hydrogel that allows gentle, reagent-free cell passaging for the long-term culture of hESCs.
- Rong Zhang
- , Heidi K. Mjoseng
- & Mark Bradley
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DJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling
Osteoblasts and endothelial cells have important roles in bone regeneration. Kim and colleagues identify the protein DJ-1 as an angiogenic and osteogenic signalling molecule involved in the cross-talk between these cells and show that DJ-1 promotes bone regeneration and fracture healing in mice.
- Jung-Min Kim
- , Hong-In Shin
- & Pann-Ghill Suh
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Preotic neural crest cells contribute to coronary artery smooth muscle involving endothelin signalling
Endothelin-1 regulates cardiovascular development by acting on neural crest cells. Here endothelin-1-deficient mice are studied, revealing that preotic neural crest cells differentiate into coronary artery smooth muscle cells through endothelin-1-dependent mechanisms.
- Yuichiro Arima
- , Sachiko Miyagawa-Tomita
- & Hiroki Kurihara
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The RB family is required for the self-renewal and survival of human embryonic stem cells
While human embryonic stem cells (ESC) hold great therapeutic promise, many aspects of their basic biology remain poorly understood. Conklin et al.show that too much or too little activation of RB family proteins is detrimental to human ESC populations and identify unique cell cycle regulatory networks in these cells.
- Jamie F. Conklin
- , Julie Baker
- & Julien Sage
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| Open AccessLaminin E8 fragments support efficient adhesion and expansion of dissociated human pluripotent stem cells
The use of animal products as culture substrates for human embryonic stem cell and induced pluripotent stem cell culture raises numerous safety concerns in a therapeutic setting. Miyazaki et al.. show that minimal fragments of human laminins provide a more effective support for the culture of these cell types.
- Takamichi Miyazaki
- , Sugiko Futaki
- & Eihachiro Kawase
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| Open AccessA kinase inhibitor screen identifies small-molecule enhancers of reprogramming and iPS cell generation
The efficiency of reprogramming somatic cells to induced pluripotent stem cells is low. To enhance reprogramming efficiency, Li and Rana used a chemical screen and identified several kinase inhibitors that enhance reprogramming, and show that blocking Aurora A, p38 and inositiol triphosphate 3-kinase signalling is important for this process.
- Zhonghan Li
- & Tariq M. Rana
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| Open AccessEndogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors
Human embryonic stem cell cultures are morphologically heterogeneous. Here, differences in Wnt signalling are shown to contribute to this heterogeneity, cells containing high levels of Wnt form endodermal and cardiac cells, whereas cells with low Wnt form neuroectodermal cells, when differentiation is induced.
- Timothy A. Blauwkamp
- , Shelly Nigam
- & Roel Nusse
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Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation
Embryonic stem cells have a shortened cell cycle that allows for rapid proliferation, but the exact mechanisms are unclear. Here, a microRNA target, Trim71, is shown to inhibit the expression of a cyclin-dependent kinase inhibitor, thus enabling the G1–S phase cell cycle transition in embryonic stem cells.
- Hao-Ming Chang
- , Natalia J. Martinez
- & Richard I. Gregory
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Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation
Chromatin in embryonic stem cells is present in an open state presumably to facilitate gene expression changes required for pluripotency and subsequent multilineage differentiation. This study describes roles for lamin A, histone acetylation and G9a-mediated histone H3 lysine 9 methylation in regulating chromatin plasticity in these cells.
- Shai Melcer
- , Hadas Hezroni
- & Eran Meshorer
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Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity
Stem cells hold great potential for therapeutic use but their supply is limited. Latilet al.isolate muscle stem cells from human and mouse cadavers after 17 and 14 days, respectively, and show that when transplanted into mice the cells can regenerate tissues.
- Mathilde Latil
- , Pierre Rocheteau
- & Fabrice Chrétien
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Differentiation of multipotent vascular stem cells contributes to vascular diseases
De-differentiation and proliferation of vascular smooth muscle cells is thought to have a dominant role in vascular remodelling. Here, Tanget al. identify a new type of multipotent vascular stem cell in the blood vessel wall that contributes to this process, thereby challenging the established hypothesis.
- Zhenyu Tang
- , Aijun Wang
- & Song Li
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| Open AccessActivin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors
Signalling inputs to neural progenitors regulate the differentiation of the stem cell pool. By analysing the mechanisms occuring during neurogenesis, Cambrayet al. report that activin is the pivotal factor regulating the differentiation of telencephalic neural precursors towards a cortical interneuron fate.
- Serafí Cambray
- , Charles Arber
- & Tristan A. Rodríguez
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| Open AccessJAK/STAT3 signalling is sufficient and dominant over antagonistic cues for the establishment of naive pluripotency
Culture conditions are critical for the successful induction of pluripotent stem cells and define whether cells are primed or naïve. Here, activation of JAK/STAT3 signalling is shown to be sufficient and dominant over antagonistic cues to enable the induction of a naïve pluripotent state in stem cells.
- Anouk L. van Oosten
- , Yael Costa
- & José C.R. Silva
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Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics
Studying the effects of extracellular matrix stiffening has been impeded because mostin vitromodels are static. Here, dynamic hydrogels are developed that stiffen in the presence of cells and are used to investigate the short-term (minutes-to-hours) and long-term (days-to-weeks) cellular responses to dynamic stiffening.
- Murat Guvendiren
- & Jason A. Burdick
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| Open AccessFully functional hair follicle regeneration through the rearrangement of stem cells and their niches
Bioengineered hair follicles can be produced from embryonic follicle germ cells, but whether these follicles can interact with the surrounding tissue and function normally is unknown. Here, bioengineered hair follicles transplanted into mouse dermis make connections with the surrounding tissue and show normal hair cycles.
- Koh-ei Toyoshima
- , Kyosuke Asakawa
- & Takashi Tsuji
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Drosophila follicle stem cells are regulated by proliferation and niche adhesion as well as mitochondria and ROS
Stem cells are thought to be tethered in their niche via adhesion molecules and the inhibition of cell differentiation. Here, the authors screened for genes required for maintainingDrosophilaovarian follicle stem cells and found their function to depend on cell proliferation, mitochondrial function and niche adhesion.
- Zhu A. Wang
- , Jianhua Huang
- & Daniel Kalderon
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Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors
Neural stem cells generate neurons in the adult hippocampus, but the dynamics of neuron production remain unclear. This study shows that stem cells produce type-2a progenitors, which do not expand as previously thought, but rather generate amplifying immature neuroblasts.
- Sebastian Lugert
- , Miriam Vogt
- & Verdon Taylor
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| Open AccessMuscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
The function of adult stem cells is diminished with age but the role this dysfunction plays in the aging process is unknown. Here, the injection of muscle-derived stem/progenitor cells from young mice rescues symptoms in progeroid mice and is shown to regenerate tissues independent of engraftment.
- Mitra Lavasani
- , Andria R. Robinson
- & Johnny Huard
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Article
| Open AccessPromotion of plasma membrane repair by vitamin E
Membrane repair of myocytes is important to prevent such disease as muscular dystrophy but the properties of this repair are not well characterised. In this study, vitamin E is shown to be important in the repair of myocyte cell membranes in cultured cells and in intact muscle.
- Amber C. Howard
- , Anna K. McNeil
- & Paul L. McNeil
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Article
| Open AccessProliferating versus differentiating stem and cancer cells exhibit distinct midbody-release behaviour
During cell division, a cytoplasmic bridge—the midbody—forms between the nascent daughter cells, but it has been unclear under which conditions this is retained by a daughter cell or released. Now, Ettinger and colleagues show that midbody-release occurs more frequently in stem cells compared with cancer cells.
- Andreas W. Ettinger
- , Michaela Wilsch-Bräuninger
- & Wieland B. Huttner
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