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Cell Stem Cell

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https://www.readbyqxmd.com/read/28215825/stage-specific-human-induced-pluripotent-stem-cells-map-the-progression-of-myeloid-transformation-to-transplantable-leukemia
#1
Andriana G Kotini, Chan-Jung Chang, Arthur Chow, Han Yuan, Tzu-Chieh Ho, Tiansu Wang, Shailee Vora, Alexander Solovyov, Chrystel Husser, Malgorzata Olszewska, Julie Teruya-Feldstein, Deepak Perumal, Virginia M Klimek, Alexandros Spyridonidis, Raajit K Rampal, Lewis Silverman, E Premkumar Reddy, Elli Papaemmanuil, Samir Parekh, Benjamin D Greenbaum, Christina S Leslie, Michael G Kharas, Eirini P Papapetrou
Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia...
February 13, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28196600/genome-editing-in-hpscs-reveals-gata6-haploinsufficiency-and-a-genetic-interaction-with-gata4-in-human-pancreatic-development
#2
Zhong-Dong Shi, Kihyun Lee, Dapeng Yang, Sadaf Amin, Nipun Verma, Qing V Li, Zengrong Zhu, Chew-Li Soh, Ritu Kumar, Todd Evans, Shuibing Chen, Danwei Huangfu
Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated genome editing coupled with human pluripotent stem cell (hPSC) directed differentiation. We found that loss of one GATA6 allele specifically affects the differentiation of human pancreatic progenitors from the early PDX1+ stage to the more mature PDX1+NKX6...
February 8, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28196601/cholinergic-signals-from-the-cns-regulate-g-csf-mediated-hsc-mobilization-from-bone-marrow-via-a-glucocorticoid-signaling-relay
#3
Halley Pierce, Dachuan Zhang, Claire Magnon, Daniel Lucas, John R Christin, Matthew Huggins, Gary J Schwartz, Paul S Frenette
Hematopoietic stem cells (HSCs) are mobilized from niches in the bone marrow (BM) to the blood circulation by the cytokine granulocyte colony-stimulating factor (G-CSF) through complex mechanisms. Among these, signals from the sympathetic nervous system regulate HSC egress via its niche, but how the brain communicates with the BM remains largely unknown. Here we show that muscarinic receptor type-1 (Chrm1) signaling in the hypothalamus promotes G-CSF-elicited HSC mobilization via hormonal priming of the hypothalamic-pituitary-adrenal (HPA) axis...
February 4, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28132834/human-ipsc-derived-neural-progenitors-are-an-effective-drug-discovery-model-for-neurological-mtdna-disorders
#4
Carmen Lorenz, Pierre Lesimple, Raul Bukowiecki, Annika Zink, Gizem Inak, Barbara Mlody, Manvendra Singh, Marcus Semtner, Nancy Mah, Karine Auré, Megan Leong, Oleksandr Zabiegalov, Ekaterini-Maria Lyras, Vanessa Pfiffer, Beatrix Fauler, Jenny Eichhorst, Burkhard Wiesner, Norbert Huebner, Josef Priller, Thorsten Mielke, David Meierhofer, Zsuzsanna Izsvák, Jochen C Meier, Frédéric Bouillaud, James Adjaye, Markus Schuelke, Erich E Wanker, Anne Lombès, Alessandro Prigione
Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment...
January 25, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28132835/recent-zika-virus-isolates-induce-premature-differentiation-of-neural-progenitors-in-human-brain-organoids
#5
Elke Gabriel, Anand Ramani, Ulrike Karow, Marco Gottardo, Karthick Natarajan, Li Ming Gooi, Gladiola Goranci-Buzhala, Oleg Krut, Franziska Peters, Milos Nikolic, Suvi Kuivanen, Essi Korhonen, Teemu Smura, Olli Vapalahti, Argyris Papantonis, Jonas Schmidt-Chanasit, Maria Riparbelli, Giuliano Callaini, Martin Krönke, Olaf Utermöhlen, Jay Gopalakrishnan
The recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors...
January 23, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28132833/nicotinamide-ameliorates-disease-phenotypes-in-a-human-ipsc-model-of-age-related-macular-degeneration
#6
Janmeet S Saini, Barbara Corneo, Justine D Miller, Thomas R Kiehl, Qingjie Wang, Nathan C Boles, Timothy A Blenkinsop, Jeffrey H Stern, Sally Temple
Age-related macular degeneration (AMD) affects the retinal pigment epithelium (RPE), a cell monolayer essential for photoreceptor survival, and is the leading cause of vision loss in the elderly. There are no disease-altering therapies for dry AMD, which is characterized by accumulation of subretinal drusen deposits and complement-driven inflammation. We report the derivation of human-induced pluripotent stem cells (hiPSCs) from patients with diagnosed AMD, including two donors with the rare ARMS2/HTRA1 homozygous genotype...
January 21, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28111200/rna-helicase-ddx5-inhibits-reprogramming-to-pluripotency-by-mirna-based-repression-of-rybp-and-its-prc1-dependent-and-independent-functions
#7
Huanhuan Li, Ping Lai, Jinping Jia, Yawei Song, Qing Xia, Kaimeng Huang, Na He, Wangfang Ping, Jiayu Chen, Zhongzhou Yang, Jiao Li, Mingze Yao, Xiaotao Dong, Jicheng Zhao, Chunhui Hou, Miguel A Esteban, Shaorong Gao, Duanqing Pei, Andrew P Hutchins, Hongjie Yao
RNA-binding proteins (RBPs), in addition to their functions in cellular homeostasis, play important roles in lineage specification and maintaining cellular identity. Despite their diverse and essential functions, which touch on nearly all aspects of RNA metabolism, the roles of RBPs in somatic cell reprogramming are poorly understood. Here we show that the DEAD-box RBP DDX5 inhibits reprogramming by repressing the expression and function of the non-canonical polycomb complex 1 (PRC1) subunit RYBP. Disrupting Ddx5 expression improves the efficiency of iPSC generation and impedes processing of miR-125b, leading to Rybp upregulation and suppression of lineage-specific genes via RYBP-dependent ubiquitination of H2AK119...
January 11, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28111201/human-ipsc-derived-cerebral-organoids-model-cellular-features-of-lissencephaly-and-reveal-prolonged-mitosis-of-outer-radial-glia
#8
Marina Bershteyn, Tomasz J Nowakowski, Alex A Pollen, Elizabeth Di Lullo, Aishwarya Nene, Anthony Wynshaw-Boris, Arnold R Kriegstein
Classical lissencephaly is a genetic neurological disorder associated with mental retardation and intractable epilepsy, and Miller-Dieker syndrome (MDS) is the most severe form of the disease. In this study, to investigate the effects of MDS on human progenitor subtypes that control neuronal output and influence brain topology, we analyzed cerebral organoids derived from control and MDS-induced pluripotent stem cells (iPSCs) using time-lapse imaging, immunostaining, and single-cell RNA sequencing. We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions...
January 9, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28111199/pericytes-of-multiple-organs-do-not-behave-as-mesenchymal-stem-cells-in%C3%A2-vivo
#9
Nuno Guimarães-Camboa, Paola Cattaneo, Yunfu Sun, Thomas Moore-Morris, Yusu Gu, Nancy D Dalton, Edward Rockenstein, Eliezer Masliah, Kirk L Peterson, William B Stallcup, Ju Chen, Sylvia M Evans
Pericytes are widely believed to function as mesenchymal stem cells (MSCs), multipotent tissue-resident progenitors with great potential for regenerative medicine. Cultured pericytes isolated from distinct tissues can differentiate into multiple cell types in vitro or following transplantation in vivo. However, the cell fate plasticity of endogenous pericytes in vivo remains unclear. Here, we show that the transcription factor Tbx18 selectively marks pericytes and vascular smooth muscle cells in multiple organs of adult mouse...
January 9, 2017: Cell Stem Cell
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
#10
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
#11
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
#12
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
#13
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
#14
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/28041894/lipid-desaturation-is-a-metabolic-marker-and-therapeutic-target-of-ovarian-cancer-stem-cells
#15
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/28017796/analysis-of-transcriptional-variability-in-a-large-human-ipsc-library-reveals-genetic-and-non-genetic-determinants-of-heterogeneity
#16
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
#17
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/28157498/rejuvenating-strategies-for-stem-cell-based-therapies-in-aging
#18
REVIEW
Joana Neves, Pedro Sousa-Victor, Heinrich Jasper
Recent advances in our understanding of tissue regeneration and the development of efficient approaches to induce and differentiate pluripotent stem cells for cell replacement therapies promise exciting avenues for treating degenerative age-related diseases. However, clinical studies and insights from model organisms have identified major roadblocks that normal aging processes impose on tissue regeneration. These new insights suggest that specific targeting of environmental niche components, including growth factors, ECM, and immune cells, and intrinsic stem cell properties that are affected by aging will be critical for the development of new strategies to improve stem cell function and optimize tissue repair processes...
February 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28157497/big-data-driven-stem-cell-science-and-tissue-engineering-vision-and-unique-opportunities
#19
Antonio Del Sol, Hans J Thiesen, Jaime Imitola, Rafael E Carazo Salas
Achieving the promises of stem cell science to generate precise disease models and designer cell samples for personalized therapeutics will require harnessing pheno-genotypic cell-level data quantitatively and predictively in the lab and clinic. Those requirements could be met by developing a Big-Data-driven stem cell science strategy and community.
February 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28157496/revealing-the-hidden-powers-that-fuel-adult-neurogenesis
#20
Weijun Feng, Hai-Kun Liu
A defining characteristic of diverse stem cell populations is their distinct metabolic state, although how these states change during adult hippocampal neurogenesis is unclear. Recently in Neuron, Beckervordersandforth et al. (2017) report that adult neurogenesis requires mitochondrial electron transport and oxidative phosphorylation and that disrupting these pathways induces premature aging phenotypes.
February 2, 2017: Cell Stem Cell
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