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Cell Stem Cell

Jose Luis Sardina, Samuel Collombet, Tian V Tian, Antonio Gómez, Bruno Di Stefano, Clara Berenguer, Justin Brumbaugh, Ralph Stadhouders, Carolina Segura-Morales, Marta Gut, Ivo G Gut, Simon Heath, Sergi Aranda, Luciano Di Croce, Konrad Hochedlinger, Denis Thieffry, Thomas Graf
Here, we report DNA methylation and hydroxymethylation dynamics at nucleotide resolution using C/EBPα-enhanced reprogramming of B cells into induced pluripotent cells (iPSCs). We observed successive waves of hydroxymethylation at enhancers, concomitant with a decrease in DNA methylation, suggesting active demethylation. Consistent with this finding, ablation of the DNA demethylase Tet2 almost completely abolishes reprogramming. C/EBPα, Klf4, and Tfcp2l1 each interact with Tet2 and recruit the enzyme to specific DNA sites...
September 6, 2018: Cell Stem Cell
Mei Wang, Xixi Liu, Gang Chang, Yidong Chen, Geng An, Liying Yan, Shuai Gao, Yanwen Xu, Yueli Cui, Ji Dong, Yuhan Chen, Xiaoying Fan, Yuqiong Hu, Ke Song, Xiaohui Zhu, Yun Gao, Zhaokai Yao, Shuhui Bian, Yu Hou, Jiahao Lu, Rui Wang, Yong Fan, Ying Lian, Wenhao Tang, Yapeng Wang, Jianqiao Liu, Lianming Zhao, Luyu Wang, Zhaoting Liu, Renpei Yuan, Yujia Shi, Boqiang Hu, Xiulian Ren, Fuchou Tang, Xiao-Yang Zhao, Jie Qiao
Spermatogenesis generates mature male gametes and is critical for the proper transmission of genetic information between generations. However, the developmental landscapes of human spermatogenesis remain unknown. Here, we performed single-cell RNA sequencing (scRNA-seq) analysis for 2,854 testicular cells from donors with normal spermatogenesis and 174 testicular cells from one nonobstructive azoospermia (NOA) donor. A hierarchical model was established, which was characterized by the sequential and stepwise development of three spermatogonia subtypes, seven spermatocyte subtypes, and four spermatid subtypes...
August 24, 2018: Cell Stem Cell
Karin Golan, Anju Kumari, Orit Kollet, Eman Khatib-Massalha, Mohana Devi Subramaniam, Zulma S Ferreira, Francesca Avemaria, Sylwia Rzeszotek, Andrés García-García, Stephanie Xie, Eugenia Flores-Figueroa, Shiri Gur-Cohen, Tomer Itkin, Aya Ludin-Tal, Hassan Massalha, Biana Bernshtein, Andrzej K Ciechanowicz, Alexander Brandis, Tevie Mehlman, Suditi Bhattacharya, Mayla Bertagna, Hui Cheng, Ekaterina Petrovich-Kopitman, Tomasz Janus, Nathali Kaushansky, Tao Cheng, Irit Sagi, Mariusz Z Ratajczak, Simón Méndez-Ferrer, John E Dick, Regina P Markus, Tsvee Lapidot
Hematopoietic stem and progenitor cells (HSPCs) tightly couple maintenance of the bone marrow (BM) reservoir, including undifferentiated long-term repopulating hematopoietic stem cells (LT-HSCs), with intensive daily production of mature leukocytes and blood replenishment. We found two daily peaks of BM HSPC activity that are initiated by onset of light and darkness providing this coupling. Both peaks follow transient elevation of BM norepinephrine and TNF secretion, which temporarily increase HSPC reactive oxygen species (ROS) levels...
August 21, 2018: Cell Stem Cell
Zhou Yu, Kaiju Jiang, Zijian Xu, Huanwei Huang, Nannan Qian, Zhiwei Lu, Daoming Chen, Ruonan Di, Tianyi Yuan, Zhenhai Du, Wei Xie, Xiaoling Lu, Huawei Li, Renjie Chai, Yong Yang, Bing Zhu, Tetsuo Kunieda, Fengchao Wang, Ting Chen
Mesenchymal niche cells instruct activity of tissue-resident stem and progenitor cell populations. Epithelial stem cells in hair follicles (HFs) have region-specific activity, which may arise from intrinsic cellular heterogeneity within mesenchymal dermal papilla (DP) cells. Here we show that expression of Hoxc genes is sufficient to reprogram mesenchymal DP cells and alter the regenerative potential of epithelial stem cells. Hoxc gene expression in adult skin dermis closely correlates with regional HF regeneration patterns...
August 8, 2018: Cell Stem Cell
Shogo Matoba, Yi Zhang
Successful cloning of monkeys, the first non-human primate species, by somatic cell nuclear transfer (SCNT) attracted worldwide attention earlier this year. Remarkably, it has taken more than 20 years since the cloning of Dolly the sheep in 1997 to achieve this feat. This success was largely due to recent understanding of epigenetic barriers that impede SCNT-mediated reprogramming and the establishment of key methods to overcome these barriers, which also allowed efficient derivation of human pluripotent stem cells for cell therapy...
July 9, 2018: Cell Stem Cell
Jeffrey H Stern, Yangzi Tian, James Funderburgh, Graziella Pellegrini, Kang Zhang, Jeffrey L Goldberg, Robin R Ali, Michael Young, Yubing Xie, Sally Temple
No abstract text is available yet for this article.
September 6, 2018: Cell Stem Cell
Chengyi Tu, Janet Zoldan
Human pluripotent stem cell-derived cardiomyocytes represent a promising cell source for cardiac repair. However, their clinical translation is hindered by limited evidence for functional benefits in primate models, potential risks for arrhythmias, and teratoma formation. A recent study by Liu et al. (2018) makes significant progress on these critical issues.
September 6, 2018: Cell Stem Cell
Tippi C MacKenzie
Fetal gene therapy using safe and effective viral vectors no longer remains a distant prospect. Recently in Nature Medicine, Massaro et al. (2018) demonstrated that prenatal intracranial injection of a viral vector results in improved neurologic function, raising the intriguing possibility that in utero gene therapy may be approaching clinical applications.
September 6, 2018: Cell Stem Cell
Ugur Sahin
Recently in Cell, Dijkstra et al. (2018) introduced a tumor organoid/lymphocyte co-culture-based approach to expand and analyze tumor-specific T cell responses in a patient-specific manner. The platform is applicable for epithelial cancers and may have significant value for clinical translation of novel personalized immunotherapies.
September 6, 2018: Cell Stem Cell
Fabrizio Simeoni, Tim C P Somervaille
Myelodysplastic syndromes are hematologic malignancies with few treatment options and a propensity to transform to acute myeloid leukemia. In this issue of Cell Stem Cell, Sun et al. (2018) report that low SIRT1 levels in myelodysplastic stem cells contribute to aberrant self-renewal through enabling hyperacetylation and reduced activity of TET2.
September 6, 2018: Cell Stem Cell
Massimo Nichane, Kyle M Loh
Why is reprogramming to generate induced pluripotent stem cells (iPSCs) a protracted and inefficient odyssey? In this issue of Cell Stem Cell, Mor et al. (2018) hypothesize that reprogramming factors paradoxically activate and inhibit pluripotency gene expression and show that eliminating Gatad2a (a NuRD corepressor complex subcomponent) rapidly and efficiently reprograms multiple cell types into iPSCs.
September 6, 2018: Cell Stem Cell
Tomohiko Okazaki, Yukiko Gotoh
Radial glia-like neural stem cells (RGLs) in the mouse hippocampus generate neurons throughout life, but RGL maintenance mechanisms remain unclear. In this issue of Cell Stem Cell, Zhou et al. (2018) identified Mfge8, a well-known mediator of the "eat-me" signal, as a factor that reinforces quiescence and protects the RGL niche from depletion.
September 6, 2018: Cell Stem Cell
Yi Zhou, Allison M Bond, Jamie E Shade, Yunhua Zhu, Chung-Ha O Davis, Xinyuan Wang, Yijing Su, Ki-Jun Yoon, Alexander T Phan, William J Chen, Justin H Oh, Nicholas Marsh-Armstrong, Kamran Atabai, Guo-Li Ming, Hongjun Song
Adult neurogenesis, arising from quiescent radial-glia-like neural stem cells (RGLs), occurs throughout life in the dentate gyrus. How neural stem cells are maintained throughout development to sustain adult mammalian neurogenesis is not well understood. Here, we show that milk fat globule-epidermal growth factor (EGF) 8 (Mfge8), a known phagocytosis factor, is highly enriched in quiescent RGLs in the dentate gyrus. Mfge8-null mice exhibit decreased adult dentate neurogenesis, and furthermore, adult RGL-specific deletion of Mfge8 leads to RGL overactivation and depletion...
September 6, 2018: Cell Stem Cell
Jie Sun, Xin He, Yinghui Zhu, Zonghui Ding, Haojie Dong, Yimei Feng, Juan Du, Hanying Wang, Xiwei Wu, Lei Zhang, Xiaochun Yu, Allen Lin, Tinisha McDonald, Dandan Zhao, Herman Wu, Wei-Kai Hua, Bin Zhang, Lifeng Feng, Kaoru Tohyama, Ravi Bhatia, Philipp Oberdoerffer, Yang Jo Chung, Peter D Aplan, Jacqueline Boultwood, Andrea Pellagatti, Samer Khaled, Marcin Kortylewski, Flavia Pichiorri, Ya-Huei Kuo, Nadia Carlesso, Guido Marcucci, Hongchuan Jin, Ling Li
Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is derived from aberrant clonal hematopoietic stem/progenitor cells (HSPCs) that persist after conventional therapies. Defining the mechanisms underlying MDS HSPC maintenance is critical for developing MDS therapy. The deacetylase SIRT1 regulates stem cell proliferation, survival, and self-renewal by deacetylating downstream proteins. Here we show that SIRT1 protein levels were downregulated in MDS HSPCs. Genetic or pharmacological activation of SIRT1 inhibited MDS HSPC functions, whereas SIRT1 deficiency enhanced MDS HSPC self-renewal...
September 6, 2018: Cell Stem Cell
Charles Hernandez, Zheng Wang, Bulat Ramazanov, Yin Tang, Sameet Mehta, Cheryl Dambrot, Yu-Wei Lee, Kaleab Tessema, Ishan Kumar, Michael Astudillo, Thomas A Neubert, Shangqin Guo, Natalia B Ivanova
As somatic cells are converted into induced pluripotent stem cells (iPSCs), their chromatin is remodeled to a pluripotent configuration with unique euchromatin-to-heterochromatin ratios, DNA methylation patterns, and enhancer and promoter status. The molecular machinery underlying this process is largely unknown. Here, we show that embryonic stem cell (ESC)-specific factors Dppa2 and Dppa4 play a key role in resetting the epigenome to a pluripotent state. They are induced in reprogramming intermediates, function as a heterodimer, and are required for efficient reprogramming of mouse and human cells...
September 6, 2018: Cell Stem Cell
Rui Gao, Chenfei Wang, Yawei Gao, Wenchao Xiu, Jiayu Chen, Xiaochen Kou, Yanhong Zhao, Yuhan Liao, Dandan Bai, Zhibin Qiao, Lei Yang, Mingzhu Wang, Ruge Zang, Xiaoyu Liu, Yanping Jia, Yanhe Li, Yalin Zhang, Jiqing Yin, Hong Wang, Xiaoping Wan, Wenqiang Liu, Yong Zhang, Shaorong Gao
Somatic cell nuclear transfer (SCNT) enables cloning of differentiated cells by reprogramming their nuclei to a totipotent state. However, successful full-term development of SCNT embryos is a low-efficiency process and arrested embryos frequently exhibit epigenetic abnormalities. Here, we generated genome-wide DNA methylation maps from mouse pre-implantation SCNT embryos. We identified widespread regions that were aberrantly re-methylated, leading to mis-expression of genes and retrotransposons important for zygotic genome activation...
September 6, 2018: Cell Stem Cell
Nofar Mor, Yoach Rais, Daoud Sheban, Shani Peles, Alejandro Aguilera-Castrejon, Asaf Zviran, Dalia Elinger, Sergey Viukov, Shay Geula, Vladislav Krupalnik, Mirie Zerbib, Elad Chomsky, Lior Lasman, Tom Shani, Jonathan Bayerl, Ohad Gafni, Suhair Hanna, Jason D Buenrostro, Tzachi Hagai, Hagit Masika, Gintautas Vainorius, Yehudit Bergman, William J Greenleaf, Miguel A Esteban, Ulrich Elling, Yishai Levin, Rada Massarwa, Yifat Merbl, Noa Novershtern, Jacob H Hanna
Mbd3, a member of nucleosome remodeling and deacetylase (NuRD) co-repressor complex, was previously identified as an inhibitor for deterministic induced pluripotent stem cell (iPSC) reprogramming, where up to 100% of donor cells successfully complete the process. NuRD can assume multiple mutually exclusive conformations, and it remains unclear whether this deterministic phenotype can be attributed to a specific Mbd3/NuRD subcomplex. Moreover, since complete ablation of Mbd3 blocks somatic cell proliferation, we aimed to explore functionally relevant alternative ways to neutralize Mbd3-dependent NuRD activity...
September 6, 2018: Cell Stem Cell
Goran Tomic, Edward Morrissey, Sarah Kozar, Shani Ben-Moshe, Alice Hoyle, Roberta Azzarelli, Richard Kemp, Chandra Sekhar Reddy Chilamakuri, Shalev Itzkovitz, Anna Philpott, Douglas J Winton
The intestinal epithelium is largely maintained by self-renewing stem cells but with apparently committed progenitors also contributing, particularly following tissue damage. However, the mechanism of, and requirement for, progenitor plasticity in mediating pathological response remain unknown. Here we show that phosphorylation of the transcription factor Atoh1 is required for both the contribution of secretory progenitors to the stem cell pool and for a robust regenerative response. As confirmed by lineage tracing, Atoh1+ cells (Atoh1(WT)CreERT2 mice) give rise to multilineage intestinal clones both in the steady state and after tissue damage...
September 6, 2018: Cell Stem Cell
Heather A Himburg, Christina M Termini, Lauren Schlussel, Jenny Kan, Michelle Li, Liman Zhao, Tiancheng Fang, Joshua P Sasine, Vivian Y Chang, John P Chute
Bone marrow (BM) perivascular stromal cells and vascular endothelial cells (ECs) are essential for hematopoietic stem cell (HSC) maintenance, but the roles of distinct niche compartments during HSC regeneration are less understood. Here we show that Leptin receptor-expressing (LepR+) BM stromal cells and ECs dichotomously regulate HSC maintenance and regeneration via secretion of pleiotrophin (PTN). BM stromal cells are the key source of PTN during steady-state hematopoiesis because its deletion from stromal cells, but not hematopoietic cells, osteoblasts, or ECs, depletes the HSC pool...
September 6, 2018: Cell Stem Cell
Taketaro Sadahiro, Mari Isomi, Naoto Muraoka, Hidenori Kojima, Sho Haginiwa, Shota Kurotsu, Fumiya Tamura, Hidenori Tani, Shugo Tohyama, Jun Fujita, Hiroyuki Miyoshi, Yoshifumi Kawamura, Naoki Goshima, Yuka W Iwasaki, Kensaku Murano, Kuniaki Saito, Mayumi Oda, Peter Andersen, Chulan Kwon, Hideki Uosaki, Hirofumi Nishizono, Keiichi Fukuda, Masaki Ieda
The mesoderm arises from pluripotent epiblasts and differentiates into multiple lineages; however, the underlying molecular mechanisms are unclear. Tbx6 is enriched in the paraxial mesoderm and is implicated in somite formation, but its function in other mesoderms remains elusive. Here, using direct reprogramming-based screening, single-cell RNA-seq in mouse embryos, and directed cardiac differentiation in pluripotent stem cells (PSCs), we demonstrated that Tbx6 induces nascent mesoderm from PSCs and determines cardiovascular and somite lineage specification via its temporal expression...
September 6, 2018: Cell Stem Cell
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