Retinoic Acid Is Required for Neural Stem and Progenitor Cell Proliferation in the Adult Hippocampus
Publication date: Available online 24 May 2018 Source:Stem Cell Reports Author(s): Swati Mishra, Kathleen K. Kelly, Nicole L. Rumian, Julie A. Siegenthaler Neural stem and precursor cell (NSPC) proliferation in the rodent adult hippocampus is essential to maintain stem cell populations and produce new neurons. Retinoic acid (RA) signaling is implicated in regulation of adult hippocampal neurogenesis, but its exact role in control of NSPC behavior has not been examined. We show RA signaling in all hippocampal NSPC subtypes and that inhibition of RA synthesis or signaling significantly decreases NSPC proliferation via abrog...
Source: Stem Cell Reports - May 24, 2018 Category: Stem Cells Source Type: research

Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating
Publication date: Available online 24 May 2018 Source:Stem Cell Reports Author(s): Véronique Giroux, Julien Stephan, Priya Chatterji, Ben Rhoades, E. Paul Wileyto, Andres J. Klein-Szanto, Christopher J. Lengner, Kathryn E. Hamilton, Anil K. Rustgi Two principal stem cell pools orchestrate the rapid cell turnover in the intestinal epithelium. Rapidly cycling Lgr5+ stem cells are intercalated between the Paneth cells at the crypt base (CBCs) and injury-resistant reserve stem cells reside above the crypt base. The intermediate filament Keratin 15 (Krt15) marks either stem cells or long-lived progenitor cells that cont...
Source: Stem Cell Reports - May 24, 2018 Category: Stem Cells Source Type: research

Generation of TCR-Expressing Innate Lymphoid-like Helper Cells that Induce Cytotoxic T Cell-Mediated Anti-leukemic Cell Response
Publication date: Available online 24 May 2018 Source:Stem Cell Reports Author(s): Norihiro Ueda, Yasushi Uemura, Rong Zhang, Shuichi Kitayama, Shoichi Iriguchi, Yohei Kawai, Yutaka Yasui, Minako Tatsumi, Tatsuki Ueda, Tian-Yi Liu, Yasutaka Mizoro, Chihiro Okada, Akira Watanabe, Mahito Nakanishi, Satoru Senju, Yasuharu Nishimura, Kiyotaka Kuzushima, Hitoshi Kiyoi, Tomoki Naoe, Shin Kaneko CD4+ T helper (Th) cell activation is essential for inducing cytotoxic T lymphocyte (CTL) responses against malignancy. We reprogrammed a Th clone specific for chronic myelogenous leukemia (CML)-derived b3a2 peptide to pluripotency and r...
Source: Stem Cell Reports - May 24, 2018 Category: Stem Cells Source Type: research

FGF2 Has Distinct Molecular Functions from GDNF in the Mouse Germline Niche
In this study, we investigated the functional differences between FGF2 and GDNF in the germline niche by providing these factors using a drug delivery system in vivo. Although both factors expanded the GFRA1+ subset of undifferentiated spermatogonia, the FGF2-expanded subset expressed RARG, which is indispensable for proper differentiation, 1.9-fold more frequently than the GDNF-expanded subset, demonstrating that FGF2 expands a differentiation-prone subset in the testis. Moreover, FGF2 acted on the germline niche to suppress RA metabolism and GDNF production, suggesting that FGF2 modifies germline niche functions to ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

NF- κB Activity Initiates Human ESC-Derived Neural Progenitor Cell Differentiation by Inducing a Metabolic Maturation Program
Publication date: Available online 19 April 2018 Source:Stem Cell Reports Author(s): Lorna M. FitzPatrick, Kate E. Hawkins, Juliette M.K.M. Delhove, Emilio Fernandez, Chiara Soldati, Louise F. Bullen, Axel Nohturfft, Simon N. Waddington, Diego L. Medina, Juan P. Bolaños, Tristan R. McKay Human neural development begins at embryonic day 19 and marks the beginning of organogenesis. Neural stem cells in the neural tube undergo profound functional, morphological, and metabolic changes during neural specification, coordinated by a combination of exogenous and endogenous cues. The temporal cell signaling activities that ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

DNA Methylation and Regulatory Elements during Chicken Germline Stem Cell Differentiation
In this study, we reported a comprehensive genome-wide DNA methylation landscape in chicken germ cells, and transcriptomic dynamics was also presented. By uncovering DNA methylation patterns on individual genes, some genes accurately modulated by DNA methylation were found to be associated with cancers and virus infection, e.g., AKT1 and CTNNB1. Chicken-unique markers were also discovered for identifying male germ cells. Importantly, integrated epigenetic mechanisms were explored during male germ cell differentiation, which provides deep insight into the epigenetic processes associated with male germ cell differentiation a...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration
Publication date: Available online 26 April 2018 Source:Stem Cell Reports Author(s): Steffen Mayerl, Manuel Schmidt, Denica Doycheva, Veerle M. Darras, Sören S. Hüttner, Anita Boelen, Theo J. Visser, Christoph Kaether, Heike Heuer, Julia von Maltzahn Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and an abnormal TH serum profile, which is fully replicated in Mct8 knockout mice and Mct8/Oatp1c1 double-knockout (M/O...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

INK4a/ARF Expression Impairs Neurogenesis in the Brain of Irradiated Mice
In conclusion, our results suggest that IR-induced p16INK4a expression is a mechanism that limits neurogenesis. Teaser Palacio et al. find that ionizing radiation induces the senescence marker INK4a/ARF in neural progenitor cells and demonstrate that such expression as a mechanism leading to loss of neurogenesis. Their results suggest that treatments looking to preserve stem cell regenerative potential, by limiting INK4a/ARF expression, may help prevent radiation-related loss of neurogenesis. (Source: Stem Cell Reports)
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Inducible Expression of GDNF in Transplanted iPSC-Derived Neural Progenitor Cells
Publication date: Available online 26 April 2018 Source:Stem Cell Reports Author(s): Aslam Abbasi Akhtar, Genevieve Gowing, Naomi Kobritz, Steve E. Savinoff, Leslie Garcia, David Saxon, Noell Cho, Gibum Kim, Colton M. Tom, Hannah Park, George Lawless, Brandon C. Shelley, Virginia B. Mattis, Joshua J. Breunig, Clive N. Svendsen Trophic factor delivery to the brain using stem cell-derived neural progenitors is a powerful way to bypass the blood-brain barrier. Protection of diseased neurons using this technology is a promising therapy for neurodegenerative diseases. Glial cell line-derived neurotrophic factor (GDNF) has prov...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Unraveling the Inconsistencies of Cardiac Differentiation Efficiency Induced by the GSK3 β Inhibitor CHIR99021 in Human Pluripotent Stem Cells
Publication date: Available online 26 April 2018 Source:Stem Cell Reports Author(s): Filip Laco, Tsung Liang Woo, Qixing Zhong, Radoslaw Szmyd, Sherwin Ting, Fahima Jaleel Khan, Christina L.L. Chai, Shaul Reuveny, Allen Chen, Steve Oh Cardiac differentiation efficiency is hampered by inconsistencies and low reproducibility. We analyzed the differentiation process of multiple human pluripotent stem cell (hPSC) lines in response to dynamic GSK3β inhibition under varying cell culture conditions. hPSCs showed strong differences in cell-cycle profiles with varying culture confluency. hPSCs with a higher percentage of cell...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

The STAT3 Target Mettl8 Regulates Mouse ESC Differentiation via Inhibiting the JNK Pathway
Publication date: Available online 26 April 2018 Source:Stem Cell Reports Author(s): Hao Gu, Dang Vinh Do, Xinyu Liu, Luang Xu, Yixun Su, Jie Min Nah, Yuqian Wong, Ying Li, Na Sheng, Gebreselassie Addisu Tilaye, Henry Yang, Huili Guo, Jun Yan, Xin-Yuan Fu The capacity of embryonic stem cells (ESCs) to differentiate into all lineages of mature organism is precisely regulated by cellular signaling factors. STAT3 is a crucial transcription factor that plays a central role in maintaining ESC identity. However, the underlying mechanism by which STAT3 directs differentiation is still not completely understood. Here, we show tha...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress
Publication date: Available online 3 May 2018 Source:Stem Cell Reports Author(s): Fumiko Honda-Ozaki, Madoka Terashima, Akira Niwa, Norikazu Saiki, Yuri Kawasaki, Haruna Ito, Akitsu Hotta, Ayako Nagahashi, Koichi Igura, Isao Asaka, Hongmei Lisa Li, Masakatsu Yanagimachi, Fukumi Furukawa, Nobuo Kanazawa, Tatsutoshi Nakahata, Megumu K. Saito Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction of the immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokines in ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Large-Scale Expansion of Human iPSC-Derived Skeletal Muscle Cells for Disease Modeling and Cell-Based Therapeutic Strategies
In this study, we found that fluorescence-activated cell sorting-purified myogenic progenitors generated from healthy controls and Pompe disease iPSCs can be robustly expanded as much as 5 × 1011-fold. At all steps during expansion, cells could be cryopreserved or differentiated into myotubes with a high fusion index. In vitro, cells were amenable to maturation into striated and contractile myofibers. Insertion of acid α-glucosidase cDNA into the AAVS1 locus in iPSCs using CRISPR/Cas9 prevented glycogen accumulation in myotubes generated from a patient with classic infantile Pompe disease. In viv...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Electrophysiologic Characterization of Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes
We report a mechanism by which RA generates an atrial-like electrophysiologic signature through the downstream regulation of calcium channel gene expression by COUP-TFII and modulation of calcium handling. Collectively, our results provide important insights into the underlying molecular mechanisms that regulate atrial-like hiPSC-CM electrophysiology and support the use of atrial-like CMs derived from hiPSCs to model AF. Teaser In this article, Darbar and colleagues identify a mechanism by which RA-guided differentiation of hiPSCs generates an atrial-like electrophysiologic signature through the downstream regulation of ca...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Differentiation of Human Pluripotent Stem Cells into Functional Endothelial Cells in Scalable Suspension Culture
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Ruth Olmer, Lena Engels, Abdulai Usman, Sandra Menke, Muhammad Nasir Hayat Malik, Frank Pessler, Gudrun Göhring, Dorothee Bornhorst, Svenja Bolten, Salim Abdelilah-Seyfried, Thomas Scheper, Henning Kempf, Robert Zweigerdt, Ulrich Martin Endothelial cells (ECs) are involved in a variety of cellular responses. As multifunctional components of vascular structures, endothelial (progenitor) cells have been utilized in cellular therapies and are required as an important cellular component of engineered tissue constructs and in vitro d...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

CXCL12/CXCR4 Signaling Enhances Human PSC-Derived Hematopoietic Progenitor  Function and Overcomes Early In Vivo Transplantation Failure
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Jennifer C. Reid, Borko Tanasijevic, Diana Golubeva, Allison L. Boyd, Deanna P. Porras, Tony J. Collins, Mickie Bhatia Human pluripotent stem cells (hPSCs) generate hematopoietic progenitor cells (HPCs) but fail to engraft xenograft models used to detect adult/somatic hematopoietic stem cells (HSCs) from donors. Recent progress to derive hPSC-derived HSCs has relied on cell-autonomous forced expression of transcription factors; however, the relationship of bone marrow to transplanted cells remains unknown. Here, we quantified a failure of...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Dissecting the Contributions of Cooperating Gene Mutations to Cancer Phenotypes and Drug Responses with Patient-Derived iPSCs
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Chan-Jung Chang, Andriana G. Kotini, Malgorzata Olszewska, Maria Georgomanoli, Julie Teruya-Feldstein, Henrik Sperber, Roberto Sanchez, Robert DeVita, Timothy J. Martins, Omar Abdel-Wahab, Robert K. Bradley, Eirini P. Papapetrou Connecting specific cancer genotypes with phenotypes and drug responses constitutes the central premise of precision oncology but is hindered by the genetic complexity and heterogeneity of primary cancer cells. Here, we use patient-derived induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing to di...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

The POU/Oct Transcription Factor Nubbin Controls the Balance of Intestinal Stem Cell Maintenance and Differentiation by Isoform-Specific Regulation
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Xiongzhuo Tang, Yunpo Zhao, Nicolas Buchon, Ylva Engström Drosophila POU/Oct transcription factors are required for many developmental processes, but their putative regulation of adult stem cell activity has not been investigated. Here, we show that Nubbin (Nub)/Pdm1, homologous to mammalian OCT1/POU2F1 and related to OCT4/POU5F1, is expressed in gut epithelium progenitor cells. We demonstrate that the nub-encoded protein isoforms, Nub-PB and Nub-PD, play opposite roles in the regulation of intestinal stem cell (ISC) maintenance and ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

X Chromosome Dosage Influences DNA Methylation Dynamics during Reprogramming to Mouse iPSCs
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Vincent Pasque, Rahul Karnik, Constantinos Chronis, Paula Petrella, Justin Langerman, Giancarlo Bonora, Juan Song, Lotte Vanheer, Anupama Sadhu Dimashkie, Alexander Meissner, Kathrin Plath A dramatic difference in global DNA methylation between male and female cells characterizes mouse embryonic stem cells (ESCs), unlike somatic cells. We analyzed DNA methylation changes during reprogramming of male and female somatic cells and in resulting induced pluripotent stem cells (iPSCs). At an intermediate reprogramming stage, somatic and pluripo...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors
This study thus reports on a robust approach to derive expandable myogenic stem/progenitor-like cells from multiple cell types. Graphical abstract Teaser In this article, Hochedlinger and colleagues reprogrammed mouse fibroblasts into induced myogenic progenitors (iMPCs) by transient expression of MyoD and treatment with small molecules. iMPCs can be extensively propagated in vitro and exhibit skeletal muscle stem/progenitor cell characteristics, including the requirement for Pax7 function as well as the ability to sustain muscle regeneration upon repeated injury. (Source: Stem Cell Reports)
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence
In this report, Lowry and colleagues found that loss of MECP2 has a more profound effect as pluripotent stem cells are terminally differentiated toward neurons. The loss of MECP2 leads to induction of P53 protein and subsequent senescence pathways including an SASP gene program, which appears to be a cause of diminished dendritic branching in Rett neurons. (Source: Stem Cell Reports)
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Interspecies Chimeras: An Interview with Rudolf Jaenisch
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 We are pleased to introduce a new feature in this issue of Stem Cell Reports in which we invite an author to share a personal narrative about his or her paper, also published in this edition. In this Q&A format, the author shares perspectives and insights into the research and its broader impact in the field, addressing questions the research may raise and its implications. (Source: Stem Cell Reports)
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

20th Anniversary of Isolation of Human Embryonic Stem Cells: A Personal Perspective
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Joseph Itskovitz-Eldor Following Jamie Thomson's lecture on primate embryonic stem cells (ESCs) at a meeting I had organized in March 1997, in Israel, to celebrate receipt of the Wolf Prize in Agriculture to my colleague and friend Neal First, frozen human embryos donated for research in Israel were shipped to Wisconsin. The five hESC lines (H1, H7, H9, H13, and H14) were established by early 1998 and transferred to my laboratory just before publication of their existence in Science, on November 6, 1998. The distribution of the cells from...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Skin Stem Cells in Silence, Action, and Cancer
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Elaine Fuchs In studying how stem cells make and maintain tissues, nearly every chapter of a cell biology textbook takes on special interest. The field even allows us to venture where no chapters have yet been written. In studying this basic problem, we are continually bombarded by nature's surprises and challenges. Stem cell biology has captured my interest for nearly my entire scientific career. Below, I focus on my laboratory's contributions to this fascinating field, to which so many friends and colleagues have made seminal discoverie...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

The Challenges of First-in-Human Stem Cell Clinical Trials: What Does This Mean for Ethics and Institutional Review Boards?
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Roger A. Barker, Melissa K. Carpenter, Stuart Forbes, Steven A. Goldman, Catriona Jamieson, Charles E. Murry, Jun Takahashi, Gordon Weir Stem cell-based clinical interventions are increasingly advancing through preclinical testing and approaching clinical trials. The complexity and diversity of these approaches, and the confusion created by unproven and untested stem cell-based “therapies,” create a growing need for a more comprehensive review of these early-stage human trials to ensure they place the patients at minimal risk ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Expanding Impact of Stem Cell Science
Publication date: 8 May 2018 Source:Stem Cell Reports, Volume 10, Issue 5 Author(s): Hans Clevers (Source: Stem Cell Reports)
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Human Induced Pluripotent Stem Cell-Derived Cardiac Cell Sheets Expressing Genetically Encoded Voltage Indicator for Pharmacological and Arrhythmia Studies
In conclusion, ArcLight mapping of hiPSC-CCSs provides a powerful tool for drug testing and arrhythmia investigation. Graphical abstract Teaser Shaheen and Shiti et al. combine hiPSC-CMs, two-dimensional cardiac tissue models, and optical mapping of a genetically encoded voltage indicator (ArcLight) to enable both short-term and repeated tissue electrophysiological phenotyping (over weeks). This allowed tracking of electrophysiological tissue remodeling over time; drug effects on conduction, repolarization, and pro-arrhythmia; and investigation of arrhythmia mechanisms and treatments. (Source: Stem Cell Reports)
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Automated Deep Learning-Based System to Identify Endothelial Cells Derived from Induced Pluripotent Stem Cells
Publication date: Available online 10 May 2018 Source:Stem Cell Reports Author(s): Dai Kusumoto, Mark Lachmann, Takeshi Kunihiro, Shinsuke Yuasa, Yoshikazu Kishino, Mai Kimura, Toshiomi Katsuki, Shogo Itoh, Tomohisa Seki, Keiichi Fukuda Deep learning technology is rapidly advancing and is now used to solve complex problems. Here, we used deep learning in convolutional neural networks to establish an automated method to identify endothelial cells derived from induced pluripotent stem cells (iPSCs), without the need for immunostaining or lineage tracing. Networks were trained to predict whether phase-contrast images contain...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

High-Level Precise Knockin of iPSCs by Simultaneous Reprogramming and Genome Editing of Human Peripheral Blood Mononuclear Cells
Publication date: Available online 10 May 2018 Source:Stem Cell Reports Author(s): Wei Wen, Xinxin Cheng, Yawen Fu, Feiying Meng, Jian-Ping Zhang, Lu Zhang, Xiao-Lan Li, Zhixue Yang, Jing Xu, Feng Zhang, Gary D. Botimer, Weiping Yuan, Changkai Sun, Tao Cheng, Xiao-Bing Zhang We have developed an improved episomal vector system for efficient generation of integration-free induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells. More recently, we reported that the use of an optimized CRISPR-Cas9 system together with a double-cut donor increases homology-directed repair-mediated precise gene knockin ef...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Hematopoietic Stem Cells but Not Multipotent Progenitors Drive Erythropoiesis during Chronic Erythroid Stress in EPO Transgenic Mice
Publication date: Available online 10 May 2018 Source:Stem Cell Reports Author(s): Rashim Pal Singh, Tatyana Grinenko, Beáta Ramasz, Kristin Franke, Mathias Lesche, Andreas Dahl, Max Gassmann, Triantafyllos Chavakis, Ian Henry, Ben Wielockx The hematopoietic stem cell (HSC) compartment consists of a small pool of cells capable of replenishing all blood cells. Although it is established that the hematopoietic system is assembled as a hierarchical organization under steady-state conditions, emerging evidence suggests that distinct differentiation pathways may exist in response to acute stress. However, it remains unc...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Oncostatin M and Kit-Ligand Control Hematopoietic Stem Cell Fate during Zebrafish Embryogenesis
Publication date: Available online 17 May 2018 Source:Stem Cell Reports Author(s): Christopher B. Mahony, Corentin Pasche, Julien Y. Bertrand Understanding the molecular pathways controlling hematopoietic stem cell specification and expansion is a necessary milestone to perform regenerative medicine. Here, we used the zebrafish model to study the role of the ckit signaling pathway in this process. We show the importance of kitb/kitlgb signaling in the specification and expansion of hematopoietic stem cells (HSCs), in the hemogenic endothelium and caudal hematopoietic tissue (CHT), respectively. Moreover, we identified the...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Signaling-Dependent Control of Apical Membrane Size and Self-Renewal in Rosette-Stage Human Neuroepithelial Stem Cells
Publication date: Available online 17 May 2018 Source:Stem Cell Reports Author(s): Jan-Philip Medelnik, Kathleen Roensch, Satoshi Okawa, Antonio del Sol, Osvaldo Chara, Levan Mchedlishvili, Elly M. Tanaka In the developing nervous system, neural stem cells are polarized and maintain an apical domain facing a central lumen. The presence of apical membrane is thought to have a profound influence on maintaining the stem cell state. With the onset of neurogenesis, cells lose their polarization, and the concomitant loss of the apical domain coincides with a loss of the stem cell identity. Little is known about the molecular si...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Identification and Single-Cell Functional Characterization of an Endodermally Biased Pluripotent Substate in Human Embryonic Stem Cells
Publication date: Available online 17 May 2018 Source:Stem Cell Reports Author(s): Thomas F. Allison, Andrew J.H. Smith, Konstantinos Anastassiadis, Jackie Sloane-Stanley, Veronica Biga, Dylan Stavish, James Hackland, Shan Sabri, Justin Langerman, Mark Jones, Kathrin Plath, Daniel Coca, Ivana Barbaric, Paul Gokhale, Peter W. Andrews Human embryonic stem cells (hESCs) display substantial heterogeneity in gene expression, implying the existence of discrete substates within the stem cell compartment. To determine whether these substates impact fate decisions of hESCs we used a GFP reporter line to investigate the properties ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

All-Optical Electrophysiology for High-Throughput Functional Characterization of a Human iPSC-Derived Motor Neuron Model of ALS
Publication date: Available online 17 May 2018 Source:Stem Cell Reports Author(s): Evangelos Kiskinis, Joel M. Kralj, Peng Zou, Eli N. Weinstein, Hongkang Zhang, Konstantinos Tsioras, Ole Wiskow, J. Alberto Ortega, Kevin Eggan, Adam E. Cohen Human induced pluripotent stem cell (iPSC)-derived neurons are an attractive substrate for modeling disease, yet the heterogeneity of these cultures presents a challenge for functional characterization by manual patch-clamp electrophysiology. Here, we describe an optimized all-optical electrophysiology, “Optopatch,” pipeline for high-throughput functional characterization ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Inductive and Selective Effects of GSK3 and MEK Inhibition on Nanog Heterogeneity in Embryonic Stem Cells
Publication date: Available online 17 May 2018 Source:Stem Cell Reports Author(s): Simon Hastreiter, Stavroula Skylaki, Dirk Loeffler, Andreas Reimann, Oliver Hilsenbeck, Philipp S. Hoppe, Daniel L. Coutu, Konstantinos D. Kokkaliaris, Michael Schwarzfischer, Konstantinos Anastassiadis, Fabian J. Theis, Timm Schroeder Embryonic stem cells (ESCs) display heterogeneous expression of pluripotency factors such as Nanog when cultured with serum and leukemia inhibitory factor (LIF). In contrast, dual inhibition of the signaling kinases GSK3 and MEK (2i) converts ESC cultures into a state with more uniform and high Nanog expressi...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Epigenetic Regulation by BAF Complexes Limits Neural Stem Cell Proliferation by Suppressing Wnt Signaling in Late Embryonic Development
Publication date: Available online 17 May 2018 Source:Stem Cell Reports Author(s): Huong Nguyen, Cemil Kerimoglu, Mehdi Pirouz, Linh Pham, Kamila A. Kiszka, Godwin Sokpor, M. Sadman Sakib, Joachim Rosenbusch, Ulrike Teichmann, Rho H. Seong, Anastassia Stoykova, Andre Fischer, Jochen F. Staiger, Tran Tuoc During early cortical development, neural stem cells (NSCs) divide symmetrically to expand the progenitor pool, whereas, in later stages, NSCs divide asymmetrically to self-renew and produce other cell types. The timely switch from such proliferative to differentiative division critically determines progenitor and neuron ...
Source: Stem Cell Reports - May 17, 2018 Category: Stem Cells Source Type: research

Inflammatory Responses and Barrier Function of Endothelial Cells Derived from Human Induced Pluripotent Stem Cells
Publication date: Available online 12 April 2018 Source:Stem Cell Reports Author(s): Oleh V. Halaidych, Christian Freund, Francijna van den Hil, Daniela C.F. Salvatori, Mara Riminucci, Christine L. Mummery, Valeria V. Orlova Several studies have reported endothelial cell (EC) derivation from human induced pluripotent stem cells (hiPSCs). However, few have explored their functional properties in depth with respect to line-to-line and batch-to-batch variability and how they relate to primary ECs. We therefore carried out accurate characterization of hiPSC-derived ECs (hiPSC-ECs) from multiple (non-integrating) hiPSC lines a...
Source: Stem Cell Reports - April 13, 2018 Category: Stem Cells Source Type: research

Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium
Publication date: Available online 12 April 2018 Source:Stem Cell Reports Author(s): Katherine B. McCauley, Konstantinos-Dionysios Alysandratos, Anjali Jacob, Finn Hawkins, Ignacio S. Caballero, Marall Vedaie, Wenli Yang, Katherine J. Slovik, Michael Morley, Gianni Carraro, Seunghyi Kook, Susan H. Guttentag, Barry R. Stripp, Edward E. Morrisey, Darrell N. Kotton Lung epithelial lineages have been difficult to maintain in pure form in vitro, and lineage-specific reporters have proven invaluable for monitoring their emergence from cultured pluripotent stem cells (PSCs). However, reporter constructs for tracking proxima...
Source: Stem Cell Reports - April 13, 2018 Category: Stem Cells Source Type: research

PITX2 Enhances the Regenerative Potential of Dystrophic Skeletal Muscle Stem Cells
Publication date: 10 April 2018 Source:Stem Cell Reports, Volume 10, Issue 4 Author(s): Daniel Vallejo, Francisco Hernández-Torres, Estefanía Lozano-Velasco, Lara Rodriguez-Outeiriño, Alejandra Carvajal, Carlota Creus, Diego Franco, Amelia Eva Aránega Duchenne muscular dystrophy (DMD), one of the most lethal genetic disorders, involves progressive muscle degeneration resulting from the absence of DYSTROPHIN. Lack of DYSTROPHIN expression in DMD has critical consequences in muscle satellite stem cells including a reduced capacity to generate myogenic precursors. Here, we demonstrate that the c-i...
Source: Stem Cell Reports - April 11, 2018 Category: Stem Cells Source Type: research

PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells
Publication date: 10 April 2018 Source:Stem Cell Reports, Volume 10, Issue 4 Author(s): Muluken S. Belew, Sonam Bhatia, Ava Keyvani Chahi, Stefan Rentas, Jonathan S. Draper, Kristin J. Hope MSI2, which is expressed predominantly in hematopoietic stem and progenitor cells (HSPCs), enforces HSPC expansion when overexpressed and is upregulated in myeloid leukemias, indicating its regulated transcription is critical to balanced self-renewal and leukemia restraint. Despite this, little is understood of the factors that enforce appropriate physiological levels of MSI2 in the blood system. Here, we define a promoter region that ...
Source: Stem Cell Reports - April 11, 2018 Category: Stem Cells Source Type: research

HDAC1 and HDAC2 Modulate TGF- β Signaling during Endothelial-to-Hematopoietic Transition
Publication date: 10 April 2018 Source:Stem Cell Reports, Volume 10, Issue 4 Author(s): Roshana Thambyrajah, Muhammad Z.H. Fadlullah, Martin Proffitt, Rahima Patel, Shaun M. Cowley, Valerie Kouskoff, Georges Lacaud The first hematopoietic stem and progenitor cells are generated during development from hemogenic endothelium (HE) through trans-differentiation. The molecular mechanisms underlying this endothelial-to-hematopoietic transition (EHT) remain poorly understood. Here, we explored the role of the epigenetic regulators HDAC1 and HDAC2 in the emergence of these first blood cells in vitro and in vivo. Loss of...
Source: Stem Cell Reports - April 11, 2018 Category: Stem Cells Source Type: research

Arginine Methylation Regulates MEIS2 Nuclear Localization to Promote Neuronal Differentiation of Adult SVZ Progenitors
Publication date: 10 April 2018 Source:Stem Cell Reports, Volume 10, Issue 4 Author(s): Jasmine Kolb, Marie Anders-Maurer, Tanja Müller, Ann-Christin Hau, Britta Moyo Grebbin, Wiebke Kallenborn-Gerhardt, Christian Behrends, Dorothea Schulte Adult neurogenesis is regulated by stem cell niche-derived extrinsic factors and cell-intrinsic regulators, yet the mechanisms by which niche signals impinge on the activity of intrinsic neurogenic transcription factors remain poorly defined. Here, we report that MEIS2, an essential regulator of adult SVZ neurogenesis, is subject to posttranslational regulation in the SVZ olfactor...
Source: Stem Cell Reports - April 11, 2018 Category: Stem Cells Source Type: research

Interleukin-6 Regulates Adult Neural Stem Cell Numbers during Normal and  Abnormal Post-natal Development
In this report, Storer and colleagues demonstrate that the circulating cytokine IL-6, which is elevated in humans in different pathological situations, can perturb neural stem cell biology after birth. They show that IL-6 signaling is essential for self-renewal and maintenance of post-natal and adult NSCs in the murine forebrain under normal homeostatic conditions. (Source: Stem Cell Reports)
Source: Stem Cell Reports - April 6, 2018 Category: Stem Cells Source Type: research

In  Vivo Genetic Manipulation of Spermatogonial Stem Cells and Their Microenvironment by Adeno-Associated Viruses
Publication date: Available online 5 April 2018 Source:Stem Cell Reports Author(s): Satoshi Watanabe, Mito Kanatsu-Shinohara, Narumi Ogonuki, Shogo Matoba, Atsuo Ogura, Takashi Shinohara Adeno-associated virus (AAV) penetrates the blood-brain barrier, but it is unknown whether AAV penetrates other tight junctions. Genetic manipulation of testis has been hampered by the basement membrane of seminiferous tubules and the blood-testis barrier (BTB), which forms between Sertoli cells and divides the tubules into basal and adluminal compartments. Here, we demonstrate in vivo genetic manipulation of spermatogonial stem cell...
Source: Stem Cell Reports - April 6, 2018 Category: Stem Cells Source Type: research

hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model
Publication date: Available online 5 April 2018 Source:Stem Cell Reports Author(s): Maroof M. Adil, Thomas Gaj, Antara T. Rao, Rishikesh U. Kulkarni, Christina M. Fuentes, Gokul N. Ramadoss, Freja K. Ekman, Evan W. Miller, David V. Schaffer Huntington disease (HD) is an inherited, progressive neurological disorder characterized by degenerating striatal medium spiny neurons (MSNs). One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by MSN progenitors derived from human pluripotent stem cells (hPSCs). While there has been remarkable progress in generating hPSC-derived MSNs, cur...
Source: Stem Cell Reports - April 6, 2018 Category: Stem Cells Source Type: research

Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia
We describe a robust method for the derivation of human microglia from stem cells, which are phenotypically and functionally comparable with primary microglia. We used stem cell-derived microglia to study the consequences of missense mutations in the microglial-expressed protein triggering receptor expressed on myeloid cells 2 (TREM2), which are causal for frontotemporal dementia-like syndrome and Nasu-Hakola disease. We find that mutant TREM2 accumulates in its immature form, does not undergo typical proteolysis, and is not trafficked to the plasma membrane. However, in the absence of plasma membrane TREM2, microglia diff...
Source: Stem Cell Reports - March 30, 2018 Category: Stem Cells Source Type: research

Far Upstream Element-Binding Protein 1 Regulates LSD1 Alternative Splicing to Promote Terminal Differentiation of Neural Progenitors
Publication date: Available online 29 March 2018 Source:Stem Cell Reports Author(s): Inah Hwang, Dongqing Cao, Yoonmi Na, Do-Yeon Kim, Tuo Zhang, Jun Yao, Hwanhee Oh, Jian Hu, Hongwu Zheng, Yu Yao, Jihye Paik Loss of a cell's ability to terminally differentiate because of mutations is a selected genetic event in tumorigenesis. Genomic analyses of low-grade glioma have reported recurrent mutations of far upstream element-binding protein 1 (FUBP1). Here, we show that FUBP1 expression is dynamically regulated during neurogenesis and that its downregulation in neural progenitors impairs terminal differentiation and promotes t...
Source: Stem Cell Reports - March 30, 2018 Category: Stem Cells Source Type: research

Promoting Myelin Repair through In  Vivo Neuroblast Reprogramming
Publication date: Available online 29 March 2018 Source:Stem Cell Reports Author(s): Bilal El Waly, Myriam Cayre, Pascale Durbec Demyelination is frequently observed in a variety of CNS insults and neurodegenerative diseases. In rodents, adult neural stem cells can generate oligodendrocytes and participate to myelin repair. However, these cells mainly produce migratory neuroblasts that differentiate in the olfactory bulb. Here, we show that, in the demyelination context, a small subset of these neuroblasts can spontaneously convert into myelinating oligodendrocytes. Furthermore, we demonstrate that the contribution of neu...
Source: Stem Cell Reports - March 30, 2018 Category: Stem Cells Source Type: research

Direct Conversion of Mouse Fibroblasts into Cholangiocyte Progenitor Cells
Publication date: Available online 29 March 2018 Source:Stem Cell Reports Author(s): Kyung Tae Lim, Jonghun Kim, Seon In Hwang, Ludi Zhang, Heonjong Han, Dasom Bae, Kee-Pyo Kim, Yi-Ping Hu, Hans R. Schöler, Insuk Lee, Lijian Hui, Dong Wook Han Disorders of the biliary epithelium, known as cholangiopathies, cause severe and irreversible liver diseases. The limited accessibility of bile duct precludes modeling of several cholangiocyte-mediated diseases. Therefore, novel approaches for obtaining functional cholangiocytes with high purity are needed. Previous work has shown that the combination of Hnf1β and Foxa3 co...
Source: Stem Cell Reports - March 30, 2018 Category: Stem Cells Source Type: research

Heterogeneity of Human Breast Stem and Progenitor Cells as Revealed by  Transcriptional Profiling
Publication date: Available online 29 March 2018 Source:Stem Cell Reports Author(s): Justin A. Colacino, Ebrahim Azizi, Michael D. Brooks, Ramdane Harouaka, Shamileh Fouladdel, Sean P. McDermott, Michael Lee, David Hill, Julie Madden, Julie Boerner, Michele L. Cote, Maureen A. Sartor, Laura S. Rozek, Max S. Wicha During development, the mammary gland undergoes extensive remodeling driven by stem cells. Breast cancers are also hierarchically organized and driven by cancer stem cells characterized by CD44+CD24low/− or aldehyde dehydrogenase (ALDH) expression. These markers identify mesenchymal and epithelial populatio...
Source: Stem Cell Reports - March 30, 2018 Category: Stem Cells Source Type: research