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Cell Stem Cell

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https://www.readbyqxmd.com/read/28089909/immunosuppression-via-loss-of-il2r%C3%AE-enhances-long-term-functional-integration-of-hesc-derived-photoreceptors-in-the-mouse-retina
#1
Jie Zhu, Helen Cifuentes, Joseph Reynolds, Deepak A Lamba
Loss of photoreceptors is a common endpoint in degenerative retinal diseases. Human pluripotent stem cells provide a potential source for photoreceptor replacement, but, even in mouse models, the efficiency and efficacy of transplantation-based repair remains poor. In this study, we examined the degree to which immune rejection contributes to these disappointing outcomes using an immunodeficient IL2 receptor γ (IL2rγ)-null mouse model. Our results show that prevention of cell rejection in the normal and degenerating retinal environment significantly improves long-term survival and integration of hESC-derived donor retinal cells...
December 29, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28089910/glioblastoma-cancer-stem-cells-evade-innate-immune-suppression-of-self-renewal-through-reduced-tlr4-expression
#2
Alvaro G Alvarado, Praveena S Thiagarajan, Erin E Mulkearns-Hubert, Daniel J Silver, James S Hale, Tyler J Alban, Soumya M Turaga, Awad Jarrar, Ofer Reizes, Michelle S Longworth, Michael A Vogelbaum, Justin D Lathia
Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals...
December 27, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28089908/human-aml-ipscs-reacquire-leukemic-properties-after-differentiation-and-model-clonal-variation-of-disease
#3
Mark P Chao, Andrew J Gentles, Susmita Chatterjee, Feng Lan, Andreas Reinisch, M Ryan Corces, Seethu Xavy, Jinfeng Shen, Daniel Haag, Soham Chanda, Rahul Sinha, Rachel M Morganti, Toshinobu Nishimura, Mohamed Ameen, Haodi Wu, Marius Wernig, Joseph C Wu, Ravindra Majeti
Understanding the relative contributions of genetic and epigenetic abnormalities to acute myeloid leukemia (AML) should assist integrated design of targeted therapies. In this study, we generated induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic mutations but reset leukemic DNA methylation/gene expression patterns. AML-iPSCs lacked leukemic potential, but when differentiated into hematopoietic cells, they reacquired the ability to give rise to leukemia in vivo and reestablished leukemic DNA methylation/gene expression patterns, including an aberrant MLL signature...
December 26, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28017795/injury-induced-senescence-enables-in%C3%A2-vivo-reprogramming-in-skeletal-muscle
#4
Aurélie Chiche, Isabelle Le Roux, Mathieu von Joest, Hiroshi Sakai, Sabela Búa Aguín, Coralie Cazin, Rana Salam, Laurence Fiette, Olinda Alegria, Patricia Flamant, Shahragim Tajbakhsh, Han Li
In vivo reprogramming is a promising approach for tissue regeneration in response to injury. Several examples of in vivo reprogramming have been reported in a variety of lineages, but some including skeletal muscle have so far proven refractory. Here, we show that acute and chronic injury enables transcription-factor-mediated reprogramming in skeletal muscle. Lineage tracing indicates that this response frequently originates from Pax7+ muscle stem cells. Injury is associated with accumulation of senescent cells, and advanced aging or local irradiation further enhanced in vivo reprogramming, while selective elimination of senescent cells reduced reprogramming efficiency...
December 22, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28041895/induction-of-expansion-and-folding-in-human-cerebral-organoids
#5
Yun Li, Julien Muffat, Attya Omer, Irene Bosch, Madeline A Lancaster, Mriganka Sur, Lee Gehrke, Juergen A Knoblich, Rudolf Jaenisch
An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and its convoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an in vitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids...
December 20, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28041896/a-quiescent-bcl11b-high-stem-cell-population-is-required-for-maintenance-of-the-mammary-gland
#6
Shang Cai, Tomer Kalisky, Debashis Sahoo, Piero Dalerba, Weiguo Feng, Yuan Lin, Dalong Qian, Angela Kong, Jeffrey Yu, Flora Wang, Elizabeth Y Chen, Ferenc A Scheeren, Angera H Kuo, Shaheen S Sikandar, Shigeo Hisamori, Linda J van Weele, Diane Heiser, Sopheak Sim, Jessica Lam, Stephen Quake, Michael F Clarke
Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. In the mammary gland, the identity and characteristics of quiescent epithelial stem cells are not clear. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. Bcl11b(high) cells are enriched for cells that can regenerate mammary glands in secondary transplants...
December 19, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28041894/lipid-desaturation-is-a-metabolic-marker-and-therapeutic-target-of-ovarian-cancer-stem-cells
#7
Junjie Li, Salvatore Condello, Jessica Thomes-Pepin, Xiaoxiao Ma, Yu Xia, Thomas D Hurley, Daniela Matei, Ji-Xin Cheng
Lack of sensitive single-cell analysis tools has limited the characterization of metabolic activity in cancer stem cells. By hyperspectral-stimulated Raman scattering imaging of single living cells and mass spectrometry analysis of extracted lipids, we report here significantly increased levels of unsaturated lipids in ovarian cancer stem cells (CSCs) as compared to non-CSCs. Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells...
December 8, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27939218/a-multi-step-transcriptional-and-chromatin-state-cascade-underlies-motor-neuron-programming-from-embryonic-stem-cells
#8
Silvia Velasco, Mahmoud M Ibrahim, Akshay Kakumanu, Görkem Garipler, Begüm Aydin, Mohamed Ahmed Al-Sayegh, Antje Hirsekorn, Farah Abdul-Rahman, Rahul Satija, Uwe Ohler, Shaun Mahony, Esteban O Mazzoni
Direct cell programming via overexpression of transcription factors (TFs) aims to control cell fate with the degree of precision needed for clinical applications. However, the regulatory steps involved in successful terminal cell fate programming remain obscure. We have investigated the underlying mechanisms by looking at gene expression, chromatin states, and TF binding during the uniquely efficient Ngn2, Isl1, and Lhx3 motor neuron programming pathway. Our analysis reveals a highly dynamic process in which Ngn2 and the Isl1/Lhx3 pair initially engage distinct regulatory regions...
December 8, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28017796/analysis-of-transcriptional-variability-in-a-large-human-ipsc-library-reveals-genetic-and-non-genetic-determinants-of-heterogeneity
#9
Ivan Carcamo-Orive, Gabriel E Hoffman, Paige Cundiff, Noam D Beckmann, Sunita L D'Souza, Joshua W Knowles, Achchhe Patel, Dimitri Papatsenko, Fahim Abbasi, Gerald M Reaven, Sean Whalen, Philip Lee, Mohammad Shahbazi, Marc Y R Henrion, Kuixi Zhu, Sven Wang, Panos Roussos, Eric E Schadt, Gaurav Pandey, Rui Chang, Thomas Quertermous, Ihor Lemischka
Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ∼50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern...
December 2, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28017794/patient-specific-ipsc-derived-endothelial-cells-uncover-pathways-that-protect-against-pulmonary-hypertension-in-bmpr2-mutation-carriers
#10
Mingxia Gu, Ning-Yi Shao, Silin Sa, Dan Li, Vittavat Termglinchan, Mohamed Ameen, Ioannis Karakikes, Gustavo Sosa, Fabian Grubert, Jaecheol Lee, Aiqin Cao, Shalina Taylor, Yu Ma, Zhixin Zhao, James Chappell, Rizwan Hamid, Eric D Austin, Joseph D Gold, Joseph C Wu, Michael P Snyder, Marlene Rabinovitch
In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes...
December 2, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27989769/adaptive-chromatin-remodeling-drives-glioblastoma-stem-cell-plasticity-and-drug-tolerance
#11
Brian B Liau, Cem Sievers, Laura K Donohue, Shawn M Gillespie, William A Flavahan, Tyler E Miller, Andrew S Venteicher, Christine H Hebert, Christopher D Carey, Scott J Rodig, Sarah J Shareef, Fadi J Najm, Peter van Galen, Hiroaki Wakimoto, Daniel P Cahill, Jeremy N Rich, Jon C Aster, Mario L Suvà, Anoop P Patel, Bradley E Bernstein
Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling...
December 2, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27939219/induced-quiescence-of-lgr5-stem-cells-in-intestinal-organoids-enables-differentiation-of-hormone-producing-enteroendocrine-cells
#12
Onur Basak, Joep Beumer, Kay Wiebrands, Hiroshi Seno, Alexander van Oudenaarden, Hans Clevers
Lgr5+ adult intestinal stem cells are highly proliferative throughout life. Single Lgr5+ stem cells can be cultured into three-dimensional organoids containing all intestinal epithelial cell types at near-normal ratios. Conditions to generate the main cell types (enterocyte, goblet cells, Paneth cells, and M cells) are well established, but signals to induce the spectrum of hormone-producing enteroendocrine cells (EECs) have remained elusive. Here, we induce Lgr5+ stem cell quiescence in vitro by blocking epidermal growth factor receptor (EGFR) or mitogen-associated protein kinase (MAPK) signaling pathways in organoids and show that their quiescent state is readily reverted...
November 17, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27939217/phb-associates-with-the-hira-complex-to-control-an-epigenetic-metabolic-circuit-in-human-escs
#13
Zhexin Zhu, Chunliang Li, Yanwu Zeng, Jianyi Ding, Zepeng Qu, Junjie Gu, Laixiang Ge, Fan Tang, Xin Huang, Chenlin Zhou, Ping Wang, Deyou Zheng, Ying Jin
The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self-renewal. PHB and HIRA act together to control global deposition of histone H3...
November 17, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27889318/neurogenic-radial-glia-like-cells-in-meninges-migrate-and-differentiate-into-functionally-integrated-neurons-in-the-neonatal-cortex
#14
Francesco Bifari, Ilaria Decimo, Annachiara Pino, Enric Llorens-Bobadilla, Sheng Zhao, Christian Lange, Gabriella Panuccio, Bram Boeckx, Bernard Thienpont, Stefan Vinckier, Sabine Wyns, Ann Bouché, Diether Lambrechts, Michele Giugliano, Mieke Dewerchin, Ana Martin-Villalba, Peter Carmeliet
Whether new neurons are added in the postnatal cerebral cortex is still debated. Here, we report that the meninges of perinatal mice contain a population of neurogenic progenitors formed during embryonic development that migrate to the caudal cortex and differentiate into Satb2(+) neurons in cortical layers II-IV. The resulting neurons are electrically functional and integrated into local microcircuits. Single-cell RNA sequencing identified meningeal cells with distinct transcriptome signatures characteristic of (1) neurogenic radial glia-like cells (resembling neural stem cells in the SVZ), (2) neuronal cells, and (3) a cell type with an intermediate phenotype, possibly representing radial glia-like meningeal cells differentiating to neuronal cells...
November 17, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27889319/cell-type-specific-chromatin-states-differentially-prime-squamous-cell-carcinoma-tumor-initiating-cells-for-epithelial-to-mesenchymal-transition
#15
Mathilde Latil, Dany Nassar, Benjamin Beck, Soufiane Boumahdi, Li Wang, Audrey Brisebarre, Christine Dubois, Erwin Nkusi, Sandrine Lenglez, Agnieszka Checinska, Alizée Vercauteren Drubbel, Michael Devos, Wim Declercq, Rui Yi, Cédric Blanpain
Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness, and resistance to therapy. Some tumors undergo EMT while others do not, which may reflect intrinsic properties of their cell of origin. However, this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show that cell-type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from interfollicular epidermis (IFE) are generally well differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential...
November 16, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27867037/cardiac-fibroblasts-adopt-osteogenic-fates-and-can-be-targeted-to-attenuate-pathological-heart-calcification
#16
Indulekha C L Pillai, Shen Li, Milagros Romay, Larry Lam, Yan Lu, Jie Huang, Nathaniel Dillard, Marketa Zemanova, Liudmilla Rubbi, Yibin Wang, Jason Lee, Ming Xia, Owen Liang, Ya-Hong Xie, Matteo Pellegrini, Aldons J Lusis, Arjun Deb
Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcification and in vivo transplantation assays, we show that cardiac fibroblasts (CFs) adopt an osteoblast cell-like fate and contribute directly to heart muscle calcification...
November 15, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27867035/two-way-conversion-between-lipogenic-and-myogenic-fibroblastic-phenotypes-marks-the-progression-and-resolution-of-lung-fibrosis
#17
Elie El Agha, Alena Moiseenko, Vahid Kheirollahi, Stijn De Langhe, Slaven Crnkovic, Grazyna Kwapiszewska, Djuro Kosanovic, Felix Schwind, Ralph T Schermuly, Ingrid Henneke, BreAnne MacKenzie, Jennifer Quantius, Susanne Herold, Aglaia Ntokou, Katrin Ahlbrecht, Rory E Morty, Andreas Günther, Werner Seeger, Saverio Bellusci
Idiopathic pulmonary fibrosis (IPF) is a form of progressive interstitial lung disease with unknown etiology. Due to a lack of effective treatment, IPF is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution...
November 14, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/28094018/single-cell-analysis-reveals-a-close-relationship-between-differentiating-dopamine-and-subthalamic-nucleus-neuronal-lineages
#18
Nigel Kee, Nikolaos Volakakis, Agnete Kirkeby, Lina Dahl, Helena Storvall, Sara Nolbrant, Laura Lahti, Åsa K Björklund, Linda Gillberg, Eliza Joodmardi, Rickard Sandberg, Malin Parmar, Thomas Perlmann
Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them...
January 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28094017/predictive-markers-guide-differentiation-to-improve-graft-outcome-in-clinical-translation-of-hesc-based-therapy-for-parkinson-s-disease
#19
Agnete Kirkeby, Sara Nolbrant, Katarina Tiklova, Andreas Heuer, Nigel Kee, Tiago Cardoso, Daniella Rylander Ottosson, Mariah J Lelos, Pedro Rifes, Stephen B Dunnett, Shane Grealish, Thomas Perlmann, Malin Parmar
Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, and predicting the long-term graft outcome already at the progenitor stage remains a challenge. Here, we took an unbiased approach to identify predictive markers expressed in dopamine neuron progenitors that correlate with graft outcome in an animal model of Parkinson's disease through gene expression analysis of >30 batches of grafted human embryonic stem cell (hESC)-derived progenitors...
January 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28094016/a-single-cell-roadmap-of-lineage-bifurcation-in-human-esc-models-of-embryonic-brain-development
#20
Zizhen Yao, John K Mich, Sherman Ku, Vilas Menon, Anne-Rachel Krostag, Refugio A Martinez, Leon Furchtgott, Heather Mulholland, Susan Bort, Margaret A Fuqua, Ben W Gregor, Rebecca D Hodge, Anu Jayabalu, Ryan C May, Samuel Melton, Angelique M Nelson, N Kiet Ngo, Nadiya V Shapovalova, Soraya I Shehata, Michael W Smith, Leah J Tait, Carol L Thompson, Elliot R Thomsen, Chaoyang Ye, Ian A Glass, Ajamete Kaykas, Shuyuan Yao, John W Phillips, Joshua S Grimley, Boaz P Levi, Yanling Wang, Sharad Ramanathan
During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development...
January 5, 2017: Cell Stem Cell
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