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Stem Cell Reports

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https://www.readbyqxmd.com/read/28330619/efficient-ex%C3%A2-vivo-engineering-and-expansion-of-highly-purified-human-hematopoietic-stem-and-progenitor-cell-populations-for-gene-therapy
#1
Erika Zonari, Giacomo Desantis, Carolina Petrillo, Francesco E Boccalatte, Maria Rosa Lidonnici, Anna Kajaste-Rudnitski, Alessandro Aiuti, Giuliana Ferrari, Luigi Naldini, Bernhard Gentner
Ex vivo gene therapy based on CD34(+) hematopoietic stem cells (HSCs) has shown promising results in clinical trials, but genetic engineering to high levels and in large scale remains challenging. We devised a sorting strategy that captures more than 90% of HSC activity in less than 10% of mobilized peripheral blood (mPB) CD34(+) cells, and modeled a transplantation protocol based on highly purified, genetically engineered HSCs co-infused with uncultured progenitor cells. Prostaglandin E2 stimulation allowed near-complete transduction of HSCs with lentiviral vectors during a culture time of less than 38 hr, mitigating the negative impact of standard culture on progenitor cell function...
March 13, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28330622/dido-as-a-switchboard-that-regulates-self-renewal-and-differentiation-in%C3%A2-embryonic-stem-cells
#2
Agnes Fütterer, Jésus de Celis, Rosana Navajas, Luis Almonacid, Julio Gutiérrez, Amaia Talavera-Gutiérrez, Cristina Pacios-Bras, Ilenia Bernascone, Fernando Martin-Belmonte, Carlos Martinéz-A
Transition from symmetric to asymmetric cell division requires precise coordination of differential gene expression. We show that embryonic stem cells (ESCs) mainly express DIDO3 and that their differentiation after leukemia inhibitory factor withdrawal requires DIDO1 expression. C-terminal truncation of DIDO3 (Dido3ΔCT) impedes ESC differentiation while retaining self-renewal; small hairpin RNA-Dido1 ESCs have the same phenotype. Dido3ΔCT ESC differentiation is rescued by ectopic expression of DIDO3, which binds the Dido locus via H3K4me3 and RNA POL II and induces DIDO1 expression...
March 10, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28330621/synergic-functions-of-mirnas-determine-neuronal-fate-of-adult-neural-stem-cells
#3
Meritxell Pons-Espinal, Emanuela de Luca, Matteo Jacopo Marzi, Ruth Beckervordersandforth, Andrea Armirotti, Francesco Nicassio, Klaus Fabel, Gerd Kempermann, Davide De Pietri Tonelli
Adult neurogenesis requires the precise control of neuronal versus astrocyte lineage determination in neural stem cells. While microRNAs (miRNAs) are critically involved in this step during development, their actions in adult hippocampal neural stem cells (aNSCs) has been unclear. As entry point to address that question we chose DICER, an endoribonuclease essential for miRNA biogenesis and other RNAi-related processes. By specific ablation of Dicer in aNSCs in vivo and in vitro, we demonstrate that miRNAs are required for the generation of new neurons, but not astrocytes, in the adult murine hippocampus...
March 10, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28330620/mad2l2-promotes-open-chromatin-in-embryonic-stem-cells-and%C3%A2-derepresses-the-dppa3-locus
#4
Ali Rahjouei, Mehdi Pirouz, Michela Di Virgilio, Dirk Kamin, Michael Kessel
The chromatin of naive embryonic stem cells (ESCs) has a largely open configuration, as evident by the lack of condensed heterochromatin and the hypomethylation of DNA. Several molecular mechanisms promoting this constellation were previously identified. Here we present evidence for an important epigenetic function of MAD2L2, a protein originally known for its role in DNA damage repair, and for its requirement in germ cell development. We demonstrate using super-resolution microscopy that numerous MAD2L2 microfoci are exclusively associated with euchromatin, similar to other factors of the DNA damage response...
March 10, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28285878/stem-cell-factors-based-identification-and-functional-properties-of-in%C3%A2-vitro-selected-subpopulations-of-malignant-mesothelioma-cells
#5
Walter Blum, László Pecze, Emanuela Felley-Bosco, Licun Wu, Marc de Perrot, Beat Schwaller
Malignant mesothelioma (MM) is an aggressive neoplasm characterized by a poor patient survival rate, because of rapid tumor recurrence following first-line therapy. Cancer stem cells (CSCs) are assumed to be responsible for initiating tumorigenesis and driving relapse after therapeutic interventions. CSC-enriched MM cell subpopulations were identified by an OCT4/SOX2 reporter approach and were characterized by (1) increased resistance to cisplatin, (2) increased sensitivity toward the FAK inhibitor VS-6063 in vitro, and (3) a higher tumor-initiating capacity in vivo in orthotopic xenograft and allograft mouse models...
March 9, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28330618/latexin-inactivation-enhances-survival-and-long-term-engraftment-of%C3%A2-hematopoietic-stem-cells-and-expands-the-entire-hematopoietic-system-in-mice
#6
Yi Liu, Cuiping Zhang, Zhenyu Li, Chi Wang, Jianhang Jia, Tianyan Gao, Gerhard Hildebrandt, Daohong Zhou, Subbarao Bondada, Peng Ji, Daret St Clair, Jinze Liu, Changguo Zhan, Hartmut Geiger, Shuxia Wang, Ying Liang
Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner...
March 7, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28330617/cd54-mediated-interaction-with-pro-inflammatory-macrophages-increases-the-immunosuppressive-function-of-human-mesenchymal-stromal-cells
#7
Nicolas Espagnolle, Adélie Balguerie, Emmanuelle Arnaud, Luc Sensebé, Audrey Varin
Mesenchymal stromal cells (MSCs) sense and modulate inflammation and represent potential clinical treatment for immune disorders. However, many details of the bidirectional interaction of MSCs and the innate immune compartment are still unsolved. Here we describe an unconventional but functional interaction between pro-inflammatory classically activated macrophages (M1MΦ) and MSCs, with CD54 playing a central role. CD54 was upregulated and enriched specifically at the contact area between M1MФ and MSCs. Moreover, the specific interaction induced calcium signaling and increased the immunosuppressive capacities of MSCs dependent on CD54 mediation...
March 7, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28285879/lineage-specification-from-prostate-progenitor-cells-requires-gata3-dependent-mitotic-spindle-orientation
#8
Maxwell E R Shafer, Alana H T Nguyen, Mathieu Tremblay, Sophie Viala, Mélanie Béland, Nicholas R Bertos, Morag Park, Maxime Bouchard
During prostate development, basal and luminal cell lineages are generated through symmetric and asymmetric divisions of bipotent basal cells. However, the extent to which spindle orientation controls division symmetry or cell fate, and the upstream factors regulating this process, are still elusive. We report that GATA3 is expressed in both prostate basal progenitor and luminal cells and that loss of GATA3 leads to a mislocalization of PRKCZ, resulting in mitotic spindle randomization during progenitor cell division...
March 7, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28285880/phenotypic-screening-identifies-modulators-of-amyloid-precursor-protein-processing-in-human-stem-cell-models-of-alzheimer-s-disease
#9
Philip W Brownjohn, James Smith, Erik Portelius, Lutgarde Serneels, Hlin Kvartsberg, Bart De Strooper, Kaj Blennow, Henrik Zetterberg, Frederick J Livesey
Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP) processing and the accumulation of APP-derived amyloid β (Aβ) peptides are key processes in Alzheimer's disease (AD). We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides...
March 6, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28285877/neurotransmitter-regulated-regeneration-in-the-zebrafish-retina
#10
Mahesh B Rao, Dominic Didiano, James G Patton
Current efforts to repair damaged or diseased mammalian retinas are inefficient and largely incapable of fully restoring vision. Conversely, the zebrafish retina is capable of spontaneous regeneration upon damage using Müller glia (MG)-derived progenitors. Understanding how zebrafish MG initiate regeneration may help develop new treatments that prompt mammalian retinas to regenerate. We show that inhibition of γ-aminobutyric acid (GABA) signaling facilitates initiation of MG proliferation. GABA levels decrease following damage, and MG are positioned to detect decreased ambient levels and undergo dedifferentiation...
March 6, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28111279/a-comprehensive-ethnically-diverse-library-of-sickle-cell-disease-specific-induced-pluripotent-stem-cells
#11
Seonmi Park, Andreia Gianotti-Sommer, Francisco Javier Molina-Estevez, Kim Vanuytsel, Nick Skvir, Amy Leung, Sarah S Rozelle, Elmutaz Mohammed Shaikho, Isabelle Weir, Zhihua Jiang, Hong-Yuan Luo, David H K Chui, Maria Stella Figueiredo, Abdulraham Alsultan, Amein Al-Ali, Paola Sebastiani, Martin H Steinberg, Gustavo Mostoslavsky, George J Murphy
Sickle cell anemia affects millions of people worldwide and is an emerging global health burden. As part of a large NIH-funded NextGen Consortium, we generated a diverse, comprehensive, and fully characterized library of sickle-cell-disease-specific induced pluripotent stem cells (iPSCs) from patients of different ethnicities, β-globin gene (HBB) haplotypes, and fetal hemoglobin (HbF) levels. iPSCs stand to revolutionize the way we study human development, model disease, and perhaps eventually, treat patients...
January 19, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28262548/notch-inhibition-enhances-cardiac-reprogramming-by-increasing-mef2c-transcriptional-activity
#12
Maria Abad, Hisayuki Hashimoto, Huanyu Zhou, Maria Gabriela Morales, Beibei Chen, Rhonda Bassel-Duby, Eric N Olson
Conversion of fibroblasts into functional cardiomyocytes represents a potential means of restoring cardiac function after myocardial infarction, but so far this process remains inefficient and little is known about its molecular mechanisms. Here we show that DAPT, a classical Notch inhibitor, enhances the conversion of mouse fibroblasts into induced cardiac-like myocytes by the transcription factors GATA4, HAND2, MEF2C, and TBX5. DAPT cooperates with AKT kinase to further augment this process, resulting in up to 70% conversion efficiency...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28262547/a-role-for-klf4-in-promoting-the-metabolic-shift-via-tcl1-during-induced-pluripotent-stem-cell-generation
#13
Ken Nishimura, Shiho Aizawa, Fransiska Liliani Nugroho, Emi Shiomitsu, Yen Thi Hai Tran, Phuong Linh Bui, Evgeniia Borisova, Yuta Sakuragi, Hitomi Takada, Akira Kurisaki, Yohei Hayashi, Aya Fukuda, Mahito Nakanishi, Koji Hisatake
Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is accompanied by morphological, functional, and metabolic alterations before acquisition of full pluripotency. Although the genome-wide effects of the reprogramming factors on gene expression are well documented, precise mechanisms by which gene expression changes evoke phenotypic responses remain to be determined. We used a Sendai virus-based system that permits reprogramming to progress in a strictly KLF4-dependent manner to screen for KLF4 target genes that are critical for the progression of reprogramming...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28262546/promotion-effects-of-mir-375-on-the-osteogenic-differentiation-of-human-adipose-derived-mesenchymal-stem-cells
#14
Si Chen, Yunfei Zheng, Shan Zhang, Lingfei Jia, Yongsheng Zhou
MicroRNA plays an important role in bone tissue engineering; however, its role and function in osteogenic differentiation warrant further investigation. In this study, we demonstrated that miR-375 was upregulated during the osteogenic differentiation of human adipose-derived mesenchymal stem cells (hASCs). Overexpression of miR-375 significantly enhanced hASCs osteogenesis both in vitro and in vivo, while knockdown of miR-375 inhibited the osteogenic differentiation of hASCs. Mechanistically, microarray analysis revealed DEPTOR as a target of miR-375 in hASCs...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28262545/generation-of-human-liver-chimeric-mice-with-hepatocytes-from-familial-hypercholesterolemia-induced-pluripotent-stem-cells
#15
Jiayin Yang, Yu Wang, Ting Zhou, Lai-Yung Wong, Xiao-Yu Tian, Xueyu Hong, Wing-Hon Lai, Ka-Wing Au, Rui Wei, Yuqing Liu, Lai-Hung Cheng, Guichan Liang, Zhijian Huang, Wenxia Fan, Ping Zhao, Xiwei Wang, David P Ibañez, Zhiwei Luo, Yingying Li, Xiaofen Zhong, Shuhan Chen, Dongye Wang, Li Li, Liangxue Lai, Baoming Qin, Xichen Bao, Andrew P Hutchins, Chung-Wah Siu, Yu Huang, Miguel A Esteban, Hung-Fat Tse
Familial hypercholesterolemia (FH) causes elevation of low-density lipoprotein cholesterol (LDL-C) in blood and carries an increased risk of early-onset cardiovascular disease. A caveat for exploration of new therapies for FH is the lack of adequate experimental models. We have created a comprehensive FH stem cell model with differentiated hepatocytes (iHeps) from human induced pluripotent stem cells (iPSCs), including genetically engineered iPSCs, for testing therapies for FH. We used FH iHeps to assess the effect of simvastatin and proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies on LDL-C uptake and cholesterol lowering in vitro...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28262544/fail-safe-system-against-potential-tumorigenicity-after-transplantation-of-ipsc-derivatives
#16
Go Itakura, Soya Kawabata, Miki Ando, Yuichiro Nishiyama, Keiko Sugai, Masahiro Ozaki, Tsuyoshi Iida, Toshiki Ookubo, Kota Kojima, Rei Kashiwagi, Kaori Yasutake, Hiromitsu Nakauchi, Hiroyuki Miyoshi, Narihito Nagoshi, Jun Kohyama, Akio Iwanami, Morio Matsumoto, Masaya Nakamura, Hideyuki Okano
Human induced pluripotent stem cells (iPSCs) are promising in regenerative medicine. However, the risks of teratoma formation and the overgrowth of the transplanted cells continue to be major hurdles that must be overcome. Here, we examined the efficacy of the inducible caspase-9 (iCaspase9) gene as a fail-safe against undesired tumorigenic transformation of iPSC-derived somatic cells. We used a lentiviral vector to transduce iCaspase9 into two iPSC lines and assessed its efficacy in vitro and in vivo. In vitro, the iCaspase9 system induced apoptosis in approximately 95% of both iPSCs and iPSC-derived neural stem/progenitor cells (iPSC-NS/PCs)...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28242217/genome-transfer-prevents-fragmentation-and-restores-developmental-potential-of-developmentally-compromised-postovulatory-aged-mouse%C3%A2-oocytes
#17
Mitsutoshi Yamada, Dieter Egli
Changes in oocyte quality can have great impact on the developmental potential of early embryos. Here we test whether nuclear genome transfer from a developmentally incompetent to a developmentally competent oocyte can restore developmental potential. Using in vitro oocyte aging as a model system we performed nuclear transfer in mouse oocytes at metaphase II or at the first interphase, and observed that development to the blastocyst stage and to term was as efficient as in control embryos. The increased developmental potential is explained primarily by correction of abnormal cytokinesis at anaphase of meiosis and mitosis, by a reduction in chromosome segregation errors, and by normalization of the localization of chromosome passenger complex components survivin and cyclin B1...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28238797/in%C3%A2-vitro-modeling-of-blood-brain-barrier-with-human-ipsc-derived-endothelial-cells-pericytes-neurons-and-astrocytes-via-notch-signaling
#18
Kohei Yamamizu, Mio Iwasaki, Hitomi Takakubo, Takumi Sakamoto, Takeshi Ikuno, Mami Miyoshi, Takayuki Kondo, Yoichi Nakao, Masato Nakagawa, Haruhisa Inoue, Jun K Yamashita
The blood-brain barrier (BBB) is composed of four cell populations, brain endothelial cells (BECs), pericytes, neurons, and astrocytes. Its role is to precisely regulate the microenvironment of the brain through selective substance crossing. Here we generated an in vitro model of the BBB by differentiating human induced pluripotent stem cells (hiPSCs) into all four populations. When the four hiPSC-derived populations were co-cultured, endothelial cells (ECs) were endowed with features consistent with BECs, including a high expression of nutrient transporters (CAT3, MFSD2A) and efflux transporters (ABCA1, BCRP, PGP, MRP5), and strong barrier function based on tight junctions...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28238796/ephrin-b1-mosaicism-drives-cell-segregation-in-craniofrontonasal-syndrome-hipsc-derived-neuroepithelial-cells
#19
Terren K Niethamer, Andrew R Larson, Audrey K O'Neill, Marina Bershteyn, Edward C Hsiao, Ophir D Klein, Jason H Pomerantz, Jeffrey O Bush
Although human induced pluripotent stem cells (hiPSCs) hold great potential for the study of human diseases affecting disparate cell types, they have been underutilized in seeking mechanistic insights into the pathogenesis of congenital craniofacial disorders. Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder caused by mutations in EFNB1 and characterized by craniofacial, skeletal, and neurological anomalies. Heterozygous females are more severely affected than hemizygous males, a phenomenon termed cellular interference that involves mosaicism for EPHRIN-B1 function...
March 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28238795/reversal-of-phenotypic-abnormalities-by-crispr-cas9-mediated-gene-correction-in-huntington-disease-patient-derived-induced-pluripotent-stem%C3%A2-cells
#20
Xiaohong Xu, Yilin Tay, Bernice Sim, Su-In Yoon, Yihui Huang, Jolene Ooi, Kagistia Hana Utami, Amin Ziaei, Bryan Ng, Carola Radulescu, Donovan Low, Alvin Yu Jin Ng, Marie Loh, Byrappa Venkatesh, Florent Ginhoux, George J Augustine, Mahmoud A Pouladi
Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls...
March 14, 2017: Stem Cell Reports
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