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Cell Stem Cell

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https://www.readbyqxmd.com/read/28943029/generation-of-mouse-and-human-organoid-forming-intestinal-progenitor-cells-by-direct-lineage-reprogramming
#1
Shizuka Miura, Atsushi Suzuki
Intestinal organoids hold great promise as a valuable tool for studying and treating intestinal diseases. The currently available sources of human intestinal organoids, tissue fragments or pluripotent stem cells, involve invasive procedures or complex differentiation protocols, respectively. Here, we show that a set of four transcription factors, Hnf4α, Foxa3, Gata6, and Cdx2, can directly reprogram mouse fibroblasts to acquire the identity of fetal intestine-derived progenitor cells (FIPCs). These induced FIPCs (iFIPCs) form spherical organoids that develop into adult-type budding organoids containing cells with intestinal stem cell properties...
September 16, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28919367/nup153-interacts-with-sox2-to-enable-bimodal-gene-regulation-and-maintenance-of-neural-progenitor-cells
#2
Tomohisa Toda, Jonathan Y Hsu, Sara B Linker, Lauren Hu, Simon T Schafer, Jerome Mertens, Filipe V Jacinto, Martin W Hetzer, Fred H Gage
Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes...
September 13, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28943028/engineering-ethics-and-self-organizing-models-of-human-development-opportunities-and-challenges
#3
Insoo Hyun
Incorporating engineering ethics early during the planning stages of organoid and gastruloid research may help prevent future confusion about the moral status of complex models of human development. However, the intrinsic self-organizing behavior of organoids and gastruloids may pose a slight challenge to this novel ethical approach.
September 12, 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/28886368/ascl1-reorganizes-chromatin-to-direct-neuronal-fate-and-suppress-tumorigenicity-of-glioblastoma-stem-cells
#5
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
No abstract text is available yet for this article.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886367/a-modular-platform-for-differentiation-of-human-pscs-into-all-major-ectodermal-lineages
#6
Jason Tchieu, Bastian Zimmer, Faranak Fattahi, Sadaf Amin, Nadja Zeltner, Shuibing Chen, Lorenz Studer
Directing the fate of human pluripotent stem cells (hPSCs) into different lineages requires variable starting conditions and components with undefined activities, introducing inconsistencies that confound reproducibility and assessment of specific perturbations. Here we introduce a simple, modular protocol for deriving the four main ectodermal lineages from hPSCs. By precisely varying FGF, BMP, WNT, and TGFβ pathway activity in a minimal, chemically defined medium, we show parallel, robust, and reproducible derivation of neuroectoderm, neural crest (NC), cranial placode (CP), and non-neural ectoderm in multiple hPSC lines, on different substrates independently of cell density...
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886366/micrornas-induce-a-permissive-chromatin-environment-that-enables-neuronal-subtype-specific-reprogramming-of-adult-human-fibroblasts
#7
Daniel G Abernathy, Woo Kyung Kim, Matthew J McCoy, Allison M Lake, Rebecca Ouwenga, Seong Won Lee, Xiaoyun Xing, Daofeng Li, Hyung Joo Lee, Robert O Heuckeroth, Joseph D Dougherty, Ting Wang, Andrew S Yoo
Directed reprogramming of human fibroblasts into fully differentiated neurons requires massive changes in epigenetic and transcriptional states. Induction of a chromatin environment permissive for acquiring neuronal subtype identity is therefore a major barrier to fate conversion. Here we show that the brain-enriched miRNAs miR-9/9(∗) and miR-124 (miR-9/9(∗)-124) trigger reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. miR-9/9(∗)-124-induced neurons (miNs) are functionally excitable and uncommitted toward specific subtypes but possess open chromatin at neuronal subtype-specific loci, suggesting that such identity can be imparted by additional lineage-specific transcription factors...
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886365/mitochondrial-replacement-techniques-remaining-ethical-challenges
#8
Annelien L Bredenoord, John B Appleby
Recent developments in the field of mitochondrial replacement technique (MRT) research and clinical practice have raised ethical concerns worldwide. We argue that the future use of MRTs requires a concerted effort among the global research and clinical community to implement and enforce responsible innovation and governance.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886364/synergistic-engineering-organoids-meet-organs-on-a-chip
#9
Takanori Takebe, Boyang Zhang, Milica Radisic
Organoid technology and organ-on-a-chip engineering have emerged as two distinct approaches for stem cell-derived 3D tissue preparation. Their strategic integration can address each approach's limitations and provide a path toward a superior, synergistic strategy of constructing tissues that will truly deliver on the promise of regenerative and precision medicine.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886363/crispr-established-editor-of-human-embryos
#10
Xiao-Jiang Li, Zhuchi Tu, Weili Yang, Shihua Li
Off-target effects and mosaicism are major concerns for applying CRISPR-Cas9 to correct genetic mutations. A recent article in Nature by Ma et al. (2017) uses an elegant CRISPR-Cas9 approach that repairs a genetic mutation in human embryos with negligible mosaicism and no off-target effects, bringing this editing tool closer to clinical application.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886362/hypothalamic-neurons-take-center-stage-in-the-neural-stem-cell-niche
#11
Julia P Andreotti, Luiza Lousado, Luiz Alexandre V Magno, Alexander Birbrair
Neural stem cells (NSCs) are a heterogeneous population of cells that generate new neurons in adult animals. Recently in Science, Paul et al. (2017) show that hypothalamic neurons control activation of a subset of NSCs in response to feeding, providing insights into how physiological cues may influence stem cell activation.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886361/survival-of-the-fittest-darwinian-selection-underpins-chemotherapy-resistance-in-aml
#12
Laura MacPherson, Mark A Dawson
Intratumor heterogeneity driving therapeutic resistance is a major challenge in cancer management. Recently in Nature, Shlush et al. (2017) provide a tour de force of genomics coupled to functional assays to demonstrate that resistance emerges from a pre-existing subpopulation of acute myeloid leukemia (AML) cells with a stem cell transcription program.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886360/putting-two-heads-together-to-build-a-better-brain
#13
John K Mich, Jennie L Close, Boaz P Levi
3D organoids enable in vitro human brain development models, but they have not yet recapitulated some essential features of brain circuit formation. Recently, several studies appearing in Nature, Nature Methods, and Cell Stem Cell generated fused organoid models of inhibitory and excitatory neuron development, which can now achieve functional circuit integration.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886359/the-trex1-dinosaur-bites-the-brain-through-the-line
#14
José Luis García Pérez, Marta E Alarcón-Riquelme
In this issue of Cell Stem Cell, Thomas et al. (2017) define the nature of accumulated ssDNA present in the neuron and astrocyte cytoplasm of TREX1 mutated stem cell-derived organoids. Accumulated ssDNAs are derived from LINE-1 endogenous retroelements, providing new clues as to the development of Aicardi-Goutières syndrome in the neural system.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886358/open-sesame-open-chromatin-regions-shed-light-onto-non-coding-risk-variants
#15
Kun Yang, Akira Sawa
Human genetics and stem cell biology have advanced neurobiology for neurodevelopmental psychiatric disorders. In this issue of Cell Stem Cell, Forrest et al. (2017) demonstrate that studying the landscape of open chromatin regions in stem cell-derived neurons helps functional interpretation of non-coding genetic variants associated with these diseases.
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28844837/prostaglandin-e1-and-its-analog-misoprostol-inhibit-human-cml-stem-cell-self-renewal-via-ep4-receptor-activation-and-repression-of-ap-1
#16
Fengyin Li, Bing He, Xiaoke Ma, Shuyang Yu, Rupali R Bhave, Steven R Lentz, Kai Tan, Monica L Guzman, Chen Zhao, Hai-Hui Xue
Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34(+) stem/progenitor cells...
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28826723/zika-virus-encoded-ns2a-disrupts-mammalian-cortical-neurogenesis-by-degrading-adherens-junction-proteins
#17
Ki-Jun Yoon, Guang Song, Xuyu Qian, Jianbo Pan, Dan Xu, Hee-Sool Rho, Nam-Shik Kim, Christa Habela, Lily Zheng, Fadi Jacob, Feiran Zhang, Emily M Lee, Wei-Kai Huang, Francisca Rojas Ringeling, Caroline Vissers, Cui Li, Ling Yuan, Koeun Kang, Sunghan Kim, Junghoon Yeo, Yichen Cheng, Sheng Liu, Zhexing Wen, Cheng-Feng Qin, Qingfeng Wu, Kimberly M Christian, Hengli Tang, Peng Jin, Zhiheng Xu, Jiang Qian, Heng Zhu, Hongjun Song, Guo-Li Ming
Zika virus (ZIKV) directly infects neural progenitors and impairs their proliferation. How ZIKV interacts with the host molecular machinery to impact neurogenesis in vivo is not well understood. Here, by systematically introducing individual proteins encoded by ZIKV into the embryonic mouse cortex, we show that expression of ZIKV-NS2A, but not Dengue virus (DENV)-NS2A, leads to reduced proliferation and premature differentiation of radial glial cells and aberrant positioning of newborn neurons. Mechanistically, in vitro mapping of protein-interactomes and biochemical analysis suggest interactions between ZIKA-NS2A and multiple adherens junction complex (AJ) components...
September 7, 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
#18
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...
September 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28803919/therapy-related-clonal-hematopoiesis-in-patients-with-non-hematologic-cancers-is-common-and-associated-with-adverse-clinical-outcomes
#19
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...
September 7, 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
#20
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...
September 7, 2017: Cell Stem Cell
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