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https://www.readbyqxmd.com/read/28445462/cell-diversity-and-network-dynamics-in-photosensitive-human-brain-organoids
#1
Giorgia Quadrato, Tuan Nguyen, Evan Z Macosko, John L Sherwood, Sung Min Yang, Daniel R Berger, Natalie Maria, Jorg Scholvin, Melissa Goldman, Justin P Kinney, Edward S Boyden, Jeff W Lichtman, Ziv M Williams, Steven A McCarroll, Paola Arlotta
In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina...
April 26, 2017: Nature
https://www.readbyqxmd.com/read/28442624/unphosphorylated-isgf3-drives-constitutive-expression-of-interferon-stimulated-genes-to-protect-against-viral-infections
#2
Wenshi Wang, Yuebang Yin, Lei Xu, Junhong Su, Fen Huang, Yijin Wang, Patrick P C Boor, Kan Chen, Wenhui Wang, Wanlu Cao, Xinying Zhou, Pengyu Liu, Luc J W van der Laan, Jaap Kwekkeboom, Maikel P Peppelenbosch, Qiuwei Pan
Interferon (IFN)-stimulated genes (ISGs) are antiviral effectors that are induced by IFNs through the formation of a tripartite transcription factor ISGF3, which is composed of IRF9 and phosphorylated forms of STAT1 and STAT2. However, we found that IFN-independent ISG expression was detectable in immortalized cell lines, primary intestinal and liver organoids, and liver tissues. The constitutive expression of ISGs was mediated by the unphosphorylated ISGF3 (U-ISGF3) complex, consisting of IRF9 together with unphosphorylated STAT1 and STAT2...
April 25, 2017: Science Signaling
https://www.readbyqxmd.com/read/28442587/combined-aurka-and-h3k9-methyltransferase-targeting-inhibits-cell-growth-by-inducing-mitotic-catastrophe
#3
Angela Mathison, Ann Salmonson, Mckenna Missfeldt, Jennifer Bintz, Monique Williams, Sarah Kossak, Asha Nair, Thiago M de Assuncao, Trace A Christensen, Navtej S Buttar, Juan L Iovanna, Robert Huebert, Gwen Lomberk
The current integrative pathobiological hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation-based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in 3D spheroids and organoids...
April 25, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28442534/oncogenic-%C3%AE-catenin-and-pik3ca-instruct-network-states-and-cancer-phenotypes-in-intestinal-organoids
#4
Pamela Riemer, Mattias Rydenfelt, Matthias Marks, Karen van Eunen, Kathrin Thedieck, Bernhard G Herrmann, Nils Blüthgen, Christine Sers, Markus Morkel
Colorectal cancer is driven by cooperating oncogenic mutations. In this study, we use organotypic cultures derived from transgenic mice inducibly expressing oncogenic β-catenin and/or PIK3CA(H1047R) to follow sequential changes in cancer-related signaling networks, intestinal cell metabolism, and physiology in a three-dimensional environment mimicking tissue architecture. Activation of β-catenin alone results in the formation of highly clonogenic cells that are nonmotile and prone to undergo apoptosis. In contrast, coexpression of stabilized β-catenin and PIK3CA(H1047R) gives rise to intestinal cells that are apoptosis-resistant, proliferative, stem cell-like, and motile...
April 25, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28442471/development-of-organoids-from-mouse-and-human-endometrium-showing-endometrial-epithelium-physiology-and-long-term-expandability
#5
Matteo Boretto, Benoit Cox, Manuel Noben, Nikolai Hendriks, Amelie Fassbender, Heleen Roose, Frédéric Amant, Dirk Timmerman, Carla Tomassetti, Arne Vanhie, Christel Meuleman, Marc Ferrante, Hugo Vankelecom
The endometrium, which is of crucial importance for reproduction, undergoes dynamic cyclic tissue remodeling. Knowledge of its molecular and cellular regulation is poor, primarily owing to a lack of study models. Here, we have established a novel and promising organoid model from both mouse and human endometrium. Dissociated endometrial tissue, embedded in Matrigel under WNT-activating conditions, swiftly formed organoid structures that showed long-term expansion capacity, and reproduced the molecular and histological phenotype of the tissue's epithelium...
April 25, 2017: Development
https://www.readbyqxmd.com/read/28442251/liquidus-tracking-large-scale-preservation-of-encapsulated-3-d-cell-cultures-using-a-vitrification-machine
#6
Eva Puschmann, Clare Selden, Steve Butler, Barry Fuller
Currently, cryo-banking of multicellular structures such as organoids, especially in large volumes at clinical scale >1 L, remains elusive for reasons such as insufficient dehydration and cryoprotectant additive (CPA(1)) penetration, slow cooling and warming rates and devitrification processes. Here we introduce the concept of Liquidus Tracking (LT) using a semi-automated process for liquid volumes of up to 450 ml including 130 ml of alginate encapsulated liver cells (AELC) that archived controlled and reversible vitrification with minimized toxicity...
April 22, 2017: Cryobiology
https://www.readbyqxmd.com/read/28439102/mecp2-regulated-mirnas-control-early-human-neurogenesis-through-differential-effects-on-erk-and-akt-signaling
#7
N Mellios, D A Feldman, S D Sheridan, J P K Ip, S Kwok, S K Amoah, B Rosen, B A Rodriguez, B Crawford, R Swaminathan, S Chou, Y Li, M Ziats, C Ernst, R Jaenisch, S J Haggarty, M Sur
Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development...
April 25, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28439013/biliary-epithelial-injury-induced-regenerative-response-by-il-33-promotes-cholangiocarcinogenesis-from-peribiliary-glands
#8
Hayato Nakagawa, Nobumi Suzuki, Yoshihiro Hirata, Yohko Hikiba, Yoku Hayakawa, Hiroto Kinoshita, Sozaburo Ihara, Koji Uchino, Yuji Nishikawa, Hideaki Ijichi, Motoyuki Otsuka, Junichi Arita, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Norihiro Kokudo, Keisuke Tateishi, Kazuhiko Koike
The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras- and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-Kras(G12D) , Tgfbr2(flox/flox) , and K19(CreERT) mice (KT-K19(CreERT) ). However, KT-K19(CreERT) mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas...
April 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28438893/revealing-the-inner-workings-of-organoids
#9
Cristina Dias, François Guillemot
No abstract text is available yet for this article.
April 24, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28436965/a-three-dimensional-model-of-human-lung-development-and-disease-from-pluripotent-stem-cells
#10
Ya-Wen Chen, Sarah Xuelian Huang, Ana Luisa Rodrigues Toste de Carvalho, Siu-Hong Ho, Mohammad Naimul Islam, Stefano Volpi, Luigi D Notarangelo, Michael Ciancanelli, Jean-Laurent Casanova, Jahar Bhattacharya, Alice F Liang, Laura M Palermo, Matteo Porotto, Anne Moscona, Hans-Willem Snoeck
Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modelling, drug discovery and regenerative medicine. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation...
April 24, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28431214/interferon-%C3%AE-released-by-activated-cd8-t-lymphocytes-impairs-the-calcium-resorption-potential-of-osteoclasts-in-calcified-human-aortic-valves
#11
Edit Nagy, Yang Lei, Eduardo Martínez-Martínez, Simon C Body, Florian Schlotter, Michael Creager, Alexander Assmann, Kamal Khabbaz, Peter Libby, Göran K Hansson, Elena Aikawa
Calcium content in patients with calcific aortic valve disease (CAVD) correlates with the severity of stenosis. In CAVD, activated T lymphocytes localize with osteoclast regions; however, the functional consequences of this association remain unknown. We hypothesized that CD8(+) T cells modulate calcification in CAVD. Explanted CAVD valves (n = 52) dissected into noncalcified and calcified portions were subjected to mRNA extraction, real-time quantitative PCR, enzyme-linked immunosorbent assay, and immunohistochemical analyses...
April 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28429766/beyond-growth-signaling-paneth-cells-metabolically-suppport-iscs
#12
Talya L Dayton, Hans Clevers
Single Lgr5 intestinal stem cells (ISCs) can be expanded in vitro into epithelial organoids or "mini-guts", self-organizing cellular structures that recreate the intestinal differentiation program; Paneth cells, which constitute the intestinal stem cell niche, secrete stem cell growth signals, and are thus essential for this process. In a recent paper published in Nature, Rodríguez-Colman et al. describe how Paneth cells may be supporting the metabolic state of ISCs.
April 21, 2017: Cell Research
https://www.readbyqxmd.com/read/28426964/ipsc-derived-human-microglia-like-cells-to-study-neurological-diseases
#13
Edsel M Abud, Ricardo N Ramirez, Eric S Martinez, Luke M Healy, Cecilia H H Nguyen, Sean A Newman, Andriy V Yeromin, Vanessa M Scarfone, Samuel E Marsh, Cristhian Fimbres, Chad A Caraway, Gianna M Fote, Abdullah M Madany, Anshu Agrawal, Rakez Kayed, Karen H Gylys, Michael D Cahalan, Brian J Cummings, Jack P Antel, Ali Mortazavi, Monica J Carson, Wayne W Poon, Mathew Blurton-Jones
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates...
April 19, 2017: Neuron
https://www.readbyqxmd.com/read/28424328/toward-off-the-shelf-adoptive-t-cell-therapies
#14
Kwanghun Chung
Artificial thymic organoids may enable more efficient engineered T cell production for immunotherapy.
April 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28424327/rig-i-mavs-and-sting-signaling-promote-gut-integrity-during-irradiation-and-immune-mediated-tissue-injury
#15
Julius C Fischer, Michael Bscheider, Gabriel Eisenkolb, Chia-Ching Lin, Alexander Wintges, Vera Otten, Caroline A Lindemans, Simon Heidegger, Martina Rudelius, Sébastien Monette, Kori A Porosnicu Rodriguez, Marco Calafiore, Sophie Liebermann, Chen Liu, Stefan Lienenklaus, Siegfried Weiss, Ulrich Kalinke, Jürgen Ruland, Christian Peschel, Yusuke Shono, Melissa Docampo, Enrico Velardi, Robert R Jenq, Alan M Hanash, Jarrod A Dudakov, Tobias Haas, Marcel R M van den Brink, Hendrik Poeck
The molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice...
April 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28423498/the-pias3-smurf2-sumoylation-pathway-suppresses-breast-cancer-organoid-invasiveness
#16
Amrita Singh Chandhoke, Ayan Chanda, Kunal Karve, Lili Deng, Shirin Bonni
Tumor metastasis profoundly reduces the survival of breast cancer patients, but the mechanisms underlying breast cancer invasiveness and metastasis are incompletely understood. Here, we report that the E3 ubiquitin ligase Smurf2 acts in a sumoylation-dependent manner to suppress the invasive behavior of MDA-MB-231 human breast cancer cell-derived organoids. We also find that the SUMO E3 ligase PIAS3 inhibits the invasive growth of breast cancer cell-derived organoids. In mechanistic studies, PIAS3 maintains breast cancer organoids in a non-invasive state via sumoylation of Smurf2...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416576/pathways-involved-in-formation-of-mammary-organoid-architecture-have-keys-to-understanding-drug-resistance-and-to-discovery-of-druggable-targets
#17
Saori Furuta, Mina J Bissell
Signals from the extracellular matrix (ECM) are received at the cell surface receptor, transmitted to the cytoskeletons, and transferred to the nucleus and chromatin for tissue- and context-specific gene expression. Cells, in return, modulate the cell shape and ECM, allowing for the maintenance of tissue homeostasis as well as for coevolution and adaptation to the environmental signals. We postulated the existence of dynamic and reciprocal interactions between the ECM and the nucleus more than three decades ago, but now these pathways have been proven experimentally thanks to the advances in imaging and cell/molecular biology techniques...
April 17, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28416282/derivation-of-human-midbrain-specific-organoids-from-neuroepithelial-stem%C3%A2-cells
#18
Anna S Monzel, Lisa M Smits, Kathrin Hemmer, Siham Hachi, Edinson Lucumi Moreno, Thea van Wuellen, Javier Jarazo, Jonas Walter, Inga Brüggemann, Ibrahim Boussaad, Emanuel Berger, Ronan M T Fleming, Silvia Bolognin, Jens C Schwamborn
Research on human brain development and neurological diseases is limited by the lack of advanced experimental in vitro models that truly recapitulate the complexity of the human brain. Here, we describe a robust human brain organoid system that is highly specific to the midbrain derived from regionally patterned neuroepithelial stem cells. These human midbrain organoids contain spatially organized groups of dopaminergic neurons, which make them an attractive model for the study of Parkinson's disease. Midbrain organoids are characterized in detail for neuronal, astroglial, and oligodendrocyte differentiation...
March 31, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28415765/stable-aneuploid-tumors-cells-are-more-sensitive-to-ttk-inhibition-than-chromosomally-unstable-cell-lines
#19
Marion A A Libouban, Jeroen A D M de Roos, Joost C M Uitdehaag, Nicole Willemsen-Seegers, Sara Mainardi, Jelle Dylus, Jos de Man, Bastiaan Tops, Jules P P Meijerink, Zuzana Storchová, Rogier C Buijsman, René H Medema, Guido J R Zaman
Inhibition of the spindle assembly checkpoint kinase TTK causes chromosome mis-segregation and tumor cell death. However, high levels of TTK correlate with chromosomal instability (CIN), which can lead to aneuploidy. We show that treatment of tumor cells with the selective small molecule TTK inhibitor NTRC 0066-0 overrides the mitotic checkpoint, irrespective of cell line sensitivity. In stable aneuploid cells NTRC 0066-0 induced acute CIN, whereas in cells with high levels of pre-existing CIN there was only a small additional fraction of cells mis-segregating their chromosomes...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414305/spop-regulates-prostate-epithelial-cell-proliferation-and-promotes-ubiquitination-and-turnover-of-c-myc-oncoprotein
#20
C Geng, S Kaochar, M Li, K Rajapakshe, W Fiskus, J Dong, C Foley, B Dong, L Zhang, O-J Kwon, S S Shah, M Bolaki, L Xin, M Ittmann, B W O'Malley, C Coarfa, N Mitsiades
The E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) is frequently dysregulated in prostate adenocarcinoma (PC), via either somatic mutations or mRNA downregulation, suggesting an important tumour suppressor function. To examine its physiologic role in the prostate epithelium in vivo, we generated mice with prostate-specific biallelic ablation of Spop. These mice exhibited increased prostate mass, prostate epithelial cell proliferation, and expression of c-MYC protein compared to littermate controls, and eventually developed prostatic intraepithelial neoplasia (PIN)...
April 17, 2017: Oncogene
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