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Cell Stem Cell

Felipe de Sousa E Melo, Frederic J de Sauvage
The intestinal epithelium is one the fastest renewing tissues in mammals and is endowed with extensive adaptability. The more traditional view of a hierarchical organization of the gut has recently given way to a more dynamic model in which various cell types within the intestinal epithelium can de-differentiate and function as an alternative source of stem cells upon tissue damage and stress conditions such as inflammation and tumorigenesis. Here, we will review the mechanistic principles and key players involved in intestinal plasticity and discuss potential therapeutic implications of cellular plasticity in regenerative medicine and cancer...
December 26, 2018: Cell Stem Cell
Katelyn E Masiuk, Jennifer Laborada, Maria Grazia Roncarolo, Roger P Hollis, Donald B Kohn
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a devastating autoimmune disease caused by mutations in FoxP3, a transcription factor required for the development and function of regulatory T cells (Treg cells). Allogeneic hematopoietic stem cell transplant (HSCT) can be curative, but suitable donors are often unavailable. Here, we demonstrate a strategy for autologous HSCT and gene therapy utilizing a lentiviral vector (LV) to restore FoxP3 expression under the control of endogenous human FOXP3 regulatory elements...
December 24, 2018: Cell Stem Cell
Wenxiang Hu, Chunjie Jiang, Dongyin Guan, Pieterjan Dierickx, Rong Zhang, Arden Moscati, Girish N Nadkarni, David J Steger, Ruth J F Loos, Cheng Hu, Weiping Jia, Raymond E Soccio, Mitchell A Lazar
Thiazolidinedione drugs (TZDs) target the transcriptional activity of peroxisome proliferator activated receptor γ (PPARγ) to reverse insulin resistance in type 2 diabetes, but side effects limit their clinical use. Here, using human adipose stem cell-derived adipocytes, we demonstrate that SNPs were enriched at sites of patient-specific PPARγ binding, which correlated with the individual-specific effects of the TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulates cholesterol metabolism, was dependent upon SNP rs4743771, which modulated PPARγ binding by influencing the genomic occupancy of its cooperating factor, NFIA...
December 23, 2018: Cell Stem Cell
Florian Villegas, Daphné Lehalle, Daniela Mayer, Melanie Rittirsch, Michael B Stadler, Marietta Zinner, Daniel Olivieri, Pierre Vabres, Laurence Duplomb-Jego, Eveline S J M De Bont, Yannis Duffourd, Floor Duijkers, Magali Avila, David Geneviève, Nada Houcinat, Thibaud Jouan, Paul Kuentz, Klaske D Lichtenbelt, Christel Thauvin-Robinet, Judith St-Onge, Julien Thevenon, Koen L I van Gassen, Mieke van Haelst, Silvana van Koningsbruggen, Daniel Hess, Sebastien A Smallwood, Jean-Baptiste Rivière, Laurence Faivre, Joerg Betschinger
Self-renewal and differentiation of pluripotent murine embryonic stem cells (ESCs) is regulated by extrinsic signaling pathways. It is less clear whether cellular metabolism instructs developmental progression. In an unbiased genome-wide CRISPR/Cas9 screen, we identified components of a conserved amino-acid-sensing pathway as critical drivers of ESC differentiation. Functional analysis revealed that lysosome activity, the Ragulator protein complex, and the tumor-suppressor protein Folliculin enable the Rag GTPases C and D to bind and seclude the bHLH transcription factor Tfe3 in the cytoplasm...
December 23, 2018: Cell Stem Cell
Jie Zhou, Jiayue Xu, Linlin Zhang, Siqi Liu, Yanni Ma, Xin Wen, Junkai Hao, Zongcheng Li, Yanli Ni, Xianlong Li, Fan Zhou, Qingqing Li, Fang Wang, Xiaoshuang Wang, Yanmin Si, Pengcheng Zhang, Chen Liu, Marisa Bartolomei, Fuchou Tang, Bing Liu, Jia Yu, Yu Lan
The generation of hematopoietic stem cells (HSCs) from embryonic endothelial precursors and pre-HSCs is precisely regulated by signaling pathways and transcription factors. Nevertheless, regulatory roles of non-coding RNAs remain unknown. Taking advantage of our ability to capture rare pre-HSCs and HSCs in vivo, we generated a single-cell landscape of long non-coding RNAs (lncRNAs) during HSC development. Combining bioinformatics and functional screening, we identified 6 lncRNAs influencing hematopoiesis in vitro...
December 20, 2018: Cell Stem Cell
Kohei Yamamizu, Mayako Fujihara, Makoto Tachibana, Shiori Katayama, Akiko Takahashi, Eiji Hara, Hiroshi Imai, Yoichi Shinkai, Jun K Yamashita
No abstract text is available yet for this article.
December 18, 2018: Cell Stem Cell
Marc Christian Thier, Oliver Hommerding, Jasper Panten, Roberta Pinna, Diego García-González, Thomas Berger, Philipp Wörsdörfer, Yassen Assenov, Roberta Scognamiglio, Adriana Przybylla, Paul Kaschutnig, Lisa Becker, Michael D Milsom, Anna Jauch, Jochen Utikal, Carl Herrmann, Hannah Monyer, Frank Edenhofer, Andreas Trumpp
We report the direct reprogramming of both adult human fibroblasts and blood cells into induced neural plate border stem cells (iNBSCs) by ectopic expression of four neural transcription factors. Self-renewing, clonal iNBSCs can be robustly expanded in defined media while retaining multilineage differentiation potential. They generate functional cell types of neural crest and CNS lineages and could be used to model a human pain syndrome via gene editing of SCN9A in iNBSCs. NBSCs can also be derived from human pluripotent stem cells and share functional and molecular features with NBSCs isolated from embryonic day 8...
December 12, 2018: Cell Stem Cell
Yu Kitadate, David J Jörg, Moe Tokue, Ayumi Maruyama, Rie Ichikawa, Soken Tsuchiya, Eri Segi-Nishida, Toshinori Nakagawa, Aya Uchida, Chiharu Kimura-Yoshida, Seiya Mizuno, Fumihiro Sugiyama, Takuya Azami, Masatsugu Ema, Chiyo Noda, Satoru Kobayashi, Isao Matsuo, Yoshiakira Kanai, Takashi Nagasawa, Yukihiko Sugimoto, Satoru Takahashi, Benjamin D Simons, Shosei Yoshida
In many tissues, homeostasis is maintained by physical contact between stem cells and an anatomically defined niche. However, how stem cell homeostasis is achieved in environments where cells are motile and dispersed among their progeny remains unknown. Using murine spermatogenesis as a model, we find that spermatogenic stem cell density is tightly regulated by the supply of fibroblast growth factors (FGFs) from lymphatic endothelial cells. We propose that stem cell homeostasis is achieved through competition for a limited supply of FGFs...
December 11, 2018: Cell Stem Cell
Asaf Zviran, Nofar Mor, Yoach Rais, Hila Gingold, Shani Peles, Elad Chomsky, Sergey Viukov, Jason D Buenrostro, Roberta Scognamiglio, Leehee Weinberger, Yair S Manor, Vladislav Krupalnik, Mirie Zerbib, Hadas Hezroni, Diego Adhemar Jaitin, David Larastiaso, Shlomit Gilad, Sima Benjamin, Ohad Gafni, Awni Mousa, Muneef Ayyash, Daoud Sheban, Jonathan Bayerl, Alejandro Aguilera-Castrejon, Rada Massarwa, Itay Maza, Suhair Hanna, Yonatan Stelzer, Igor Ulitsky, William J Greenleaf, Amos Tanay, Andreas Trumpp, Ido Amit, Yitzhak Pilpel, Noa Novershtern, Jacob H Hanna
The epigenetic dynamics of induced pluripotent stem cell (iPSC) reprogramming in correctly reprogrammed cells at high resolution and throughout the entire process remain largely undefined. Here, we characterize conversion of mouse fibroblasts into iPSCs using Gatad2a-Mbd3/NuRD-depleted and highly efficient reprogramming systems. Unbiased high-resolution profiling of dynamic changes in levels of gene expression, chromatin engagement, DNA accessibility, and DNA methylation were obtained. We identified two distinct and synergistic transcriptional modules that dominate successful reprogramming, which are associated with cell identity and biosynthetic genes...
December 10, 2018: Cell Stem Cell
Piyush B Gupta, Ievgenia Pastushenko, Adam Skibinski, Cedric Blanpain, Charlotte Kuperwasser
Our traditional understanding of phenotypic plasticity in adult somatic cells comprises dedifferentiation and transdifferentiation in the context of tissue regeneration or wound healing. Although dedifferentiation is central to tissue repair and stemness, this process inherently carries the risk of cancer initiation. Consequently, recent research suggests phenotypic plasticity as a new paradigm for understanding cancer initiation, progression, and resistance to therapy. Here, we discuss how cells acquire plasticity and the role of plasticity in initiating cancer, cancer progression, and metastasis and in developing therapy resistance...
November 27, 2018: Cell Stem Cell
Mikhail Osipovitch, Andrea Asenjo Martinez, John N Mariani, Adam Cornwell, Simrat Dhaliwal, Lisa Zou, Devin Chandler-Militello, Su Wang, Xiaojie Li, Sarah-Jehanne Benraiss, Robert Agate, Andrea Lampp, Abdellatif Benraiss, Martha S Windrem, Steven A Goldman
Huntington's disease (HD) is characterized by hypomyelination and neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs) derived from mutant Huntingtin (mHTT) embryos or normal controls and performed RNA sequencing (RNA-seq) to assess mHTT-dependent changes in gene expression. In human GPCs (hGPCs) derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply downregulated relative to normal hESC GPCs; NKX2...
November 23, 2018: Cell Stem Cell
Stefan Frank, Gaurav Ahuja, Deniz Bartsch, Nicole Russ, Wenjie Yao, Joseph Chao-Chung Kuo, Jens-Peter Derks, Vijay Suresh Akhade, Yulia Kargapolova, Theodore Georgomanolis, Jan-Erik Messling, Marie Gramm, Lilija Brant, Rizwan Rehimi, Natalia Emilse Vargas, Alina Kuroczik, Tsun-Po Yang, Raja Ghazanfar Ali Sahito, Julia Franzen, Juergen Hescheler, Agapios Sachinidis, Martin Peifer, Alvaro Rada-Iglesias, Meena Kanduri, Ivan G Costa, Chandrasekhar Kanduri, Argyris Papantonis, Leo Kurian
Human protein-coding genes are often accompanied by divergently transcribed non-coding RNAs whose functions, especially in cell fate decisions, are poorly understood. Using an hESC-based cardiac differentiation model, we define a class of divergent lncRNAs, termed yin yang lncRNAs (yylncRNAs), that mirror the cell-type-specific expression pattern of their protein-coding counterparts. yylncRNAs are preferentially encoded from the genomic loci of key developmental cell fate regulators. Most yylncRNAs are spliced polyadenylated transcripts showing comparable expression patterns in vivo in mouse and in human embryos...
November 21, 2018: Cell Stem Cell
Jianing Fu, Julien Zuber, Mercedes Martinez, Brittany Shonts, Aleksandar Obradovic, Hui Wang, Sai-Ping Lau, Amy Xia, Elizabeth E Waffarn, Kristjana Frangaj, Thomas M Savage, Michael T Simpson, Suxiao Yang, Xinzheng V Guo, Michelle Miron, Takashi Senda, Kortney Rogers, Adeeb Rahman, Siu-Hong Ho, Yufeng Shen, Adam Griesemer, Donna L Farber, Tomoaki Kato, Megan Sykes
Human intestinal transplantation often results in long-term mixed chimerism of donor and recipient blood in transplant patients. We followed the phenotypes of chimeric peripheral blood cells in 21 patients receiving intestinal allografts over 5 years. Donor lymphocyte phenotypes suggested a contribution of hematopoietic stem and progenitor cells (HSPCs) from the graft. Surprisingly, we detected donor-derived HSPCs in intestinal mucosa, Peyer's patches, mesenteric lymph nodes, and liver. Human gut HSPCs are phenotypically similar to bone marrow HSPCs and have multilineage differentiation potential in vitro and in vivo...
November 21, 2018: Cell Stem Cell
Charmaine Lang, Kieran R Campbell, Brent J Ryan, Phillippa Carling, Moustafa Attar, Jane Vowles, Olga V Perestenko, Rory Bowden, Fahd Baig, Meike Kasten, Michele T Hu, Sally A Cowley, Caleb Webber, Richard Wade-Martins
Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson's disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression...
November 20, 2018: Cell Stem Cell
Matthew J Carr, Jeremy S Toma, Adam P W Johnston, Patrick E Steadman, Scott A Yuzwa, Neemat Mahmud, Paul W Frankland, David R Kaplan, Freda D Miller
Peripheral innervation plays an important role in regulating tissue repair and regeneration. Here we provide evidence that injured peripheral nerves provide a reservoir of mesenchymal precursor cells that can directly contribute to murine digit tip regeneration and skin repair. In particular, using single-cell RNA sequencing and lineage tracing, we identify transcriptionally distinct mesenchymal cell populations within the control and injured adult nerve, including neural crest-derived cells in the endoneurium with characteristics of mesenchymal precursor cells...
November 19, 2018: Cell Stem Cell
Guido van Mierlo, René A M Dirks, Laura De Clerck, Arie B Brinkman, Michelle Huth, Susan L Kloet, Nehmé Saksouk, Leonie I Kroeze, Sander Willems, Matthias Farlik, Christoph Bock, Joop H Jansen, Dieter Deforce, Michiel Vermeulen, Jérôme Déjardin, Maarten Dhaenens, Hendrik Marks
The pluripotent ground state is defined as a basal state free of epigenetic restrictions, which influence lineage specification. While naive embryonic stem cells (ESCs) can be maintained in a hypomethylated state with open chromatin when grown using two small-molecule inhibitors (2i)/leukemia inhibitory factor (LIF), in contrast to serum/LIF-grown ESCs that resemble early post-implantation embryos, broader features of the ground-state pluripotent epigenome are not well understood. We identified epigenetic features of mouse ESCs cultured using 2i/LIF or serum/LIF by proteomic profiling of chromatin-associated complexes and histone modifications...
November 14, 2018: Cell Stem Cell
Kyle B Jones, Sachiko Furukawa, Pauline Marangoni, Hongfang Ma, Henry Pinkard, Rebecca D'Urso, Rapolas Zilionis, Allon M Klein, Ophir D Klein
The oral mucosa is one of the most rapidly dividing tissues in the body and serves as a barrier to physical and chemical insults from mastication, food, and microorganisms. Breakdown of this barrier can lead to significant morbidity and potentially life-threatening infections for patients. Determining the identity and organization of oral epithelial progenitor cells (OEPCs) is therefore paramount to understanding their roles in homeostasis and disease. Using lineage tracing and label retention experiments, we show that rapidly dividing OEPCs are located broadly within the basal layer of the mucosa throughout the oral cavity...
November 7, 2018: Cell Stem Cell
Jens Preussner, Jiasheng Zhong, Krishnamoorthy Sreenivasan, Stefan Günther, Thomas Engleitner, Carsten Künne, Markus Glatzel, Roland Rad, Mario Looso, Thomas Braun, Johnny Kim
The identity of tumor-initiating cells in many cancer types is unknown. Tumors often express genes associated with embryonic development, although the contributions of zygotic programs to tumor initiation and formation are poorly understood. Here, we show that regeneration-induced loss of quiescence in p53-deficient muscle stem cells (MuSCs) results in rhabdomyosarcoma formation with 100% penetrance. Genomic analyses of purified tumor cells revealed spontaneous and discrete oncogenic amplifications in MuSCs that drive tumorigenesis, including, but not limited to, the amplification of the cleavage-stage Dux transcription factor (TF) Duxbl...
November 1, 2018: Cell Stem Cell
Atsutaka Minagawa, Toshiaki Yoshikawa, Masaki Yasukawa, Akitsu Hotta, Mihoko Kunitomo, Shoichi Iriguchi, Maiko Takiguchi, Yoshiaki Kassai, Eri Imai, Yutaka Yasui, Yohei Kawai, Rong Zhang, Yasushi Uemura, Hiroyuki Miyoshi, Mahito Nakanishi, Akira Watanabe, Akira Hayashi, Kei Kawana, Tomoyuki Fujii, Tetsuya Nakatsura, Shin Kaneko
Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8αβ T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) α chain gene during the CD4/CD8 double positive stage of in vitro differentiation...
November 1, 2018: Cell Stem Cell
Haojia Wu, Kohei Uchimura, Erinn L Donnelly, Yuhei Kirita, Samantha A Morris, Benjamin D Humphreys
Kidney organoids derived from human pluripotent stem cells have great utility for investigating organogenesis and disease mechanisms and, potentially, as a replacement tissue source, but how closely organoids derived from current protocols replicate adult human kidney is undefined. We compared two directed differentiation protocols by single-cell transcriptomics of 83,130 cells from 65 organoids with single-cell transcriptomes of fetal and adult kidney cells. Both protocols generate a diverse range of kidney cells with differing ratios, but organoid-derived cell types are immature, and 10%-20% of cells are non-renal...
November 1, 2018: Cell Stem Cell
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