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Cell Stem Cell

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https://www.readbyqxmd.com/read/28803919/therapy-related-clonal-hematopoiesis-in-patients-with-non-hematologic-cancers-is-common-and-associated-with-adverse-clinical-outcomes
#1
Catherine C Coombs, Ahmet Zehir, Sean M Devlin, Ashwin Kishtagari, Aijazuddin Syed, Philip Jonsson, David M Hyman, David B Solit, Mark E Robson, José Baselga, Maria E Arcila, Marc Ladanyi, Martin S Tallman, Ross L Levine, Michael F Berger
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use...
August 9, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28803920/open-chromatin-profiling-in-hipsc-derived-neurons-prioritizes-functional-noncoding-psychiatric-risk-variants-and-highlights-neurodevelopmental-loci
#2
Marc P Forrest, Hanwen Zhang, Winton Moy, Heather McGowan, Catherine Leites, Leonardo E Dionisio, Zihui Xu, Jianxin Shi, Alan R Sanders, William J Greenleaf, Chad A Cowan, Zhiping P Pang, Pablo V Gejman, Peter Penzes, Jubao Duan
Most disease variants lie within noncoding genomic regions, making their functional interpretation challenging. Because chromatin openness strongly influences transcriptional activity, we hypothesized that cell-type-specific open chromatin regions (OCRs) might highlight disease-relevant noncoding sequences. To investigate, we mapped global OCRs in neurons differentiating from hiPSCs, a cellular model for studying neurodevelopmental disorders such as schizophrenia (SZ). We found that the OCRs are highly dynamic and can stratify GWAS-implicated SZ risk variants...
August 4, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28803918/modeling-of-trex1-dependent-autoimmune-disease-using-human-stem-cells-highlights-l1-accumulation-as-a-source-of-neuroinflammation
#3
Charles A Thomas, Leon Tejwani, Cleber A Trujillo, Priscilla D Negraes, Roberto H Herai, Pinar Mesci, Angela Macia, Yanick J Crow, Alysson R Muotri
Three-prime repair exonuclease 1 (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1...
August 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28757360/fusion-of-regionally-specified-hpsc-derived-organoids-models-human-brain-development-and-interneuron-migration
#4
Yangfei Xiang, Yoshiaki Tanaka, Benjamin Patterson, Young-Jin Kang, Gubbi Govindaiah, Naomi Roselaar, Bilal Cakir, Kun-Yong Kim, Adam P Lombroso, Sung-Min Hwang, Mei Zhong, Edouard G Stanley, Andrew G Elefanty, Janice R Naegele, Sang-Hun Lee, Sherman M Weissman, In-Hyun Park
Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively...
July 26, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777946/engineered-epidermal-progenitor-cells-can-correct-diet-induced-obesity-and-diabetes
#5
Jiping Yue, Xuewen Gou, Yuanyuan Li, Barton Wicksteed, Xiaoyang Wu
Somatic gene therapy is a promising approach for treating otherwise terminal or debilitating diseases. The human skin is a promising conduit for genetic engineering, as it is the largest and most accessible organ, epidermal autografts and tissue-engineered skin equivalents have been successfully deployed in clinical applications, and skin epidermal stem/progenitor cells for generating such grafts are easy to obtain and expand in vitro. Here, we develop skin grafts from mouse and human epidermal progenitors that were engineered by CRISPR-mediated genome editing to controllably release GLP-1 (glucagon-like peptide 1), a critical incretin that regulates blood glucose homeostasis...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777945/long-term-engraftment-of-primary-bone-marrow-stromal-cells-repairs-niche-damage-and-improves-hematopoietic-stem-cell-transplantation
#6
Jean-Paul Abbuehl, Zuzana Tatarova, Werner Held, Joerg Huelsken
Hematopoietic stem cell (HSC) transplantation represents a curative treatment for various hematological disorders. However, delayed reconstitution of innate and adaptive immunity often causes fatal complications. HSC maintenance and lineage differentiation are supported by stromal niches, and we now find that bone marrow stroma cells (BMSCs) are severely and permanently damaged by the pre-conditioning irradiation required for efficient HSC transplantation. Using mouse models, we show that stromal insufficiency limits the number of donor-derived HSCs and B lymphopoiesis...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777944/human-pluripotent-stem-cell-derived-atrial-and-ventricular-cardiomyocytes-develop-from-distinct-mesoderm-populations
#7
Jee Hoon Lee, Stephanie I Protze, Zachary Laksman, Peter H Backx, Gordon M Keller
The ability to direct the differentiation of human pluripotent stem cells (hPSCs) to the different cardiomyocyte subtypes is a prerequisite for modeling specific forms of cardiovascular disease in vitro and for developing novel therapies to treat them. Here we have investigated the development of the human atrial and ventricular lineages from hPSCs, and we show that retinoic acid signaling at the mesoderm stage of development is required for atrial specification. Analyses of early developmental stages revealed that ventricular and atrial cardiomyocytes derive from different mesoderm populations that can be distinguished based on CD235a and RALDH2 expression, respectively...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777943/mesenchymal-stem-cells-in-fibrotic-disease
#8
REVIEW
Elie El Agha, Rafael Kramann, Rebekka K Schneider, Xiaokun Li, Werner Seeger, Benjamin D Humphreys, Saverio Bellusci
Fibrosis is associated with organ failure and high mortality and is commonly characterized by aberrant myofibroblast accumulation. Investigating the cellular origin of myofibroblasts in various diseases is thus a promising strategy for developing targeted anti-fibrotic treatments. Recent studies using genetic lineage tracing technology have implicated diverse organ-resident perivascular mesenchymal stem cell (MSC)-like cells and bone marrow-MSCs in myofibroblast generation during fibrosis development. In this Review, we give an overview of the emerging role of MSCs and MSC-like cells in myofibroblast-mediated fibrotic disease in the kidney, lung, heart, liver, skin, and bone marrow...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777942/combining-hipscs-and-human-genetics-major-applications-in-drug-development
#9
Jin Zhang, Hu Li, Alan Trounson, Joseph C Wu, Paul Nioi
Merging iPSC models and human genetic research has opened up new avenues in understanding disease mechanisms and target biology, which facilitate exciting translation of this research to many areas of drug development. We highlight recent applications of these combined disciplines and discuss remaining challenges and potential solutions.
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777941/cholangiocytes-no-longer-cinderellas-to-the-hepatic-regenerative-response
#10
Malcolm R Alison
Biliary ductal cells proliferate from the portal areas of chronically damaged livers, but their significance to regeneration has been controversial. A recent article in Nature by Raven et al. (2017) now shows that blocking hepatocyte replication is essential for the hepatic differentiation of ductular cells after liver damage.
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777940/a-little-bit-of-guidance-mini-brains-on-their-route-to-adolescence
#11
Philipp Koch, Julia Ladewig
Cerebral organoids represent a new model in which to study human brain development outside the human body. Recently in Nature Biotechnology, Lancaster et al. (2017) tackled the lack of reproducibility, tissue homogeneity, and complexity of this system by bioengineering organoids to establish the next generation of human mini brains.
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777939/do-not-adjust-your-mind-the-fault-is-in-your-glia
#12
Robin J M Franklin, Edward T Bullmore
Glia have been implicated in schizophrenia, although whether they play a primary role is uncertain. In this issue of Cell Stem Cell, Windrem et al. (2017) transplant human glial progenitors from schizophrenia patients into mouse brains, which develop abnormalities and behaviors characteristic of schizophrenia, thereby suggesting a primary role for glia in the complex disease pathogenesis.
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777938/engineering-skin-with-skinny-genes
#13
Anika Böttcher, Heiko Lickert, Matthias Tschöp
The increasing prevalence of obesity and diabetes is an urgent worldwide health challenge. Now in Cell Stem Cell, Yue et al. (2017) report a proof-of-concept study using genetically engineered skin transplants that produce the incretin GLP-1 to prevent diet-induced obesity, suggesting a powerful approach for treating metabolic disorders.
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28777937/upstairs-downstairs-atrial-and-ventricular-cardiac-myocytes-from-human-pluripotent-stem-cells
#14
Michael D Schneider
Cardiomyocyte creation by human pluripotent stem cells (hPSCs) has generated opportunities for heart repair, disease modeling, and drug development. In this issue of Cell Stem Cell,Lee et al. (2017) report prospective markers of atrial versus ventricular myocyte formation from hPSCs and their use in directed differentiation of cardiac sub-lineages.
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28736217/high-content-screening-in-hpsc-neural-progenitors-identifies-drug-candidates-that-inhibit-zika-virus-infection-in-fetal-like-organoids-and-adult-brain
#15
Ting Zhou, Lei Tan, Gustav Y Cederquist, Yujie Fan, Brigham J Hartley, Suranjit Mukherjee, Mark Tomishima, Kristen J Brennand, Qisheng Zhang, Robert E Schwartz, Todd Evans, Lorenz Studer, Shuibing Chen
Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28736216/pathogen-induced-tlr4-trif-innate-immune-signaling-in-hematopoietic-stem-cells-promotes-proliferation-but-reduces-competitive-fitness
#16
Hitoshi Takizawa, Kristin Fritsch, Larisa V Kovtonyuk, Yasuyuki Saito, Chakradhar Yakkala, Kurt Jacobs, Akshay K Ahuja, Massimo Lopes, Annika Hausmann, Wolf-Dietrich Hardt, Álvaro Gomariz, César Nombela-Arrieta, Markus G Manz
Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28736215/human-ipsc-glial-mouse-chimeras-reveal-glial-contributions-to-schizophrenia
#17
Martha S Windrem, Mikhail Osipovitch, Zhengshan Liu, Janna Bates, Devin Chandler-Militello, Lisa Zou, Jared Munir, Steven Schanz, Katherine McCoy, Robert H Miller, Su Wang, Maiken Nedergaard, Robert L Findling, Paul J Tesar, Steven A Goldman
In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28712938/ascl1-reorganizes-chromatin-to-direct-neuronal-fate-and-suppress-tumorigenicity-of-glioblastoma-stem-cells
#18
Nicole I Park, Paul Guilhamon, Kinjal Desai, Rochelle F McAdam, Ellen Langille, Madlen O'Connor, Xiaoyang Lan, Heather Whetstone, Fiona J Coutinho, Robert J Vanner, Erick Ling, Panagiotis Prinos, Lilian Lee, Hayden Selvadurai, Gurnit Atwal, Michelle Kushida, Ian D Clarke, Veronique Voisin, Michael D Cusimano, Mark Bernstein, Sunit Das, Gary Bader, Cheryl H Arrowsmith, Stephane Angers, Xi Huang, Mathieu Lupien, Peter B Dirks
Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1(hi) GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1(lo) GSCs do not...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28648365/direct-reprogramming-of-fibroblasts-via-a-chemically-induced-xen-like-state
#19
Xiang Li, Defang Liu, Yantao Ma, Xiaomin Du, Junzhan Jing, Lipeng Wang, Bingqing Xie, Da Sun, Shaoqiang Sun, Xueqin Jin, Xu Zhang, Ting Zhao, Jingyang Guan, Zexuan Yi, Weifeng Lai, Ping Zheng, Zhuo Huang, Yanzhong Chang, Zhen Chai, Jun Xu, Hongkui Deng
Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28686871/retinoic-acid-puts-hematopoietic-stem-cells-back-to-sleep
#20
Alexandra Rundberg Nilsson, Cornelis Jan Pronk
Dormant hematopoietic stem cells (dHSCs) display superior serial reconstitution capacity compared to active HSCs, although their role in normal hematopoiesis has not been thoroughly investigated. Recently in Cell, Cabezas-Wallscheid et al. (2017) demonstrate involvement of retinoic acid signaling in murine dHSCs for preservation of the HSC pool.
July 6, 2017: Cell Stem Cell
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