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Cell Stem Cell

Lara Planas-Paz, Tianliang Sun, Monika Pikiolek, Nadire R Cochran, Sebastian Bergling, Vanessa Orsini, Zinger Yang, Frederic Sigoillot, Jasna Jetzer, Maryam Syed, Marilisa Neri, Sven Schuierer, Lapo Morelli, Philipp S Hoppe, Wibke Schwarzer, Carlos M Cobos, John L Alford, Le Zhang, Rachel Cuttat, Annick Waldt, Nicole Carballido-Perrig, Florian Nigsch, Bernd Kinzel, Thomas B Nicholson, Yi Yang, Xiaohong Mao, Luigi M Terracciano, Carsten Russ, John S Reece-Hoyes, Caroline Gubser Keller, Andreas W Sailer, Tewis Bouwmeester, Linda E Greenbaum, Jesse J Lugus, Feng Cong, Gregory McAllister, Gregory R Hoffman, Guglielmo Roma, Jan S Tchorz
Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/β-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing...
May 7, 2019: Cell Stem Cell
Hisayuki Hashimoto, Zhaoning Wang, Glynnis A Garry, Venkat S Malladi, Giovanni A Botten, Wenduo Ye, Huanyu Zhou, Marco Osterwalder, Diane E Dickel, Axel Visel, Ning Liu, Rhonda Bassel-Duby, Eric N Olson
The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements...
May 6, 2019: Cell Stem Cell
Brian J Pepe-Mooney, Michael T Dill, Anna Alemany, Jose Ordovas-Montanes, Yuki Matsushita, Anuradha Rao, Anushna Sen, Makoto Miyazaki, Sayeepriyadarshini Anakk, Paul A Dawson, Noriaki Ono, Alex K Shalek, Alexander van Oudenaarden, Fernando D Camargo
The liver can substantially regenerate after injury, with both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs), playing important roles in parenchymal regeneration. Beyond metabolic functions, BECs exhibit substantial plasticity and in some contexts can drive hepatic repopulation. Here, we performed single-cell RNA sequencing to examine BEC and hepatocyte heterogeneity during homeostasis and after injury. Instead of evidence for a transcriptionally defined progenitor-like BEC cell, we found significant homeostatic BEC heterogeneity that reflects fluctuating activation of a YAP-dependent program...
May 1, 2019: Cell Stem Cell
Hana Benchetrit, Mohammad Jaber, Valery Zayat, Shulamit Sebban, Avital Pushett, Kirill Makedonski, Zvi Zakheim, Ahmed Radwan, Noam Maoz, Rachel Lasry, Noa Renous, Michal Inbar, Oren Ram, Tommy Kaplan, Yosef Buganim
Following fertilization, totipotent cells undergo asymmetric cell divisions, resulting in three distinct cell types in the late pre-implantation blastocyst: epiblast (Epi), primitive endoderm (PrE), and trophectoderm (TE). Here, we aim to understand whether these three cell types can be induced from fibroblasts by one combination of transcription factors. By utilizing a sophisticated fluorescent knockin reporter system, we identified a combination of five transcription factors, Gata3, Eomes, Tfap2c, Myc, and Esrrb, that can reprogram fibroblasts into induced pluripotent stem cells (iPSCs), induced trophoblast stem cells (iTSCs), and induced extraembryonic endoderm stem cells (iXENs) , concomitantly...
April 24, 2019: Cell Stem Cell
Jasmin Paris, Marcos Morgan, Joana Campos, Gary J Spencer, Alena Shmakova, Ivayla Ivanova, Christopher Mapperley, Hannah Lawson, David A Wotherspoon, Catarina Sepulveda, Milica Vukovic, Lewis Allen, Annika Sarapuu, Andrea Tavosanis, Amelie V Guitart, Arnaud Villacreces, Christian Much, Junho Choe, Ali Azar, Louie N van de Lagemaat, Douglas Vernimmen, Ali Nehme, Frederic Mazurier, Tim C P Somervaille, Richard I Gregory, Dónal O'Carroll, Kamil R Kranc
Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA m6 A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6 A transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis...
April 24, 2019: Cell Stem Cell
Audrey Der Vartanian, Marie Quétin, Stéphanie Michineau, Frédéric Auradé, Shinichiro Hayashi, Christelle Dubois, Didier Rocancourt, Bernadette Drayton-Libotte, Anikó Szegedi, Margaret Buckingham, Simon J Conway, Marianne Gervais, Frédéric Relaix
Muscle satellite cells (MuSCs) are the quiescent muscle stem cells required for adult skeletal muscle repair. The impact of environmental stress such as pollution on MuSC behavior remains unexplored. We evaluated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, a ubiquitous and highly toxic pollutant, on MuSCs by combining in vivo mouse molecular genetic models with ex vivo studies. While all MuSCs express the transcription factor PAX7, we show that a subset also express PAX3 and exhibit resistance to environmental stress...
April 12, 2019: Cell Stem Cell
Annarita Scaramozza, Dongsu Park, Swapna Kollu, Isabel Beerman, Xuefeng Sun, Derrick J Rossi, Charles P Lin, David T Scadden, Colin Crist, Andrew S Brack
Stem cell heterogeneity is recognized as functionally relevant for tissue homeostasis and repair. The identity, context dependence, and regulation of skeletal muscle satellite cell (SC) subsets remains poorly understood. We identify a minor subset of Pax7+ SCs that is indelibly marked by an inducible Mx1-Cre transgene in vivo, is enriched for Pax3 expression, and has reduced ROS (reactive oxygen species) levels. Mx1+ SCs possess potent stem cell activity upon transplantation but minimally contribute to endogenous muscle repair, due to their relative low abundance...
April 12, 2019: Cell Stem Cell
Tüzer Kalkan, Susanne Bornelöv, Carla Mulas, Evangelia Diamanti, Tim Lohoff, Meryem Ralser, Sjors Middelkamp, Patrick Lombard, Jennifer Nichols, Austin Smith
The gene regulatory network (GRN) of naive mouse embryonic stem cells (ESCs) must be reconfigured to enable lineage commitment. TCF3 sanctions rewiring by suppressing components of the ESC transcription factor circuitry. However, TCF3 depletion only delays and does not prevent transition to formative pluripotency. Here, we delineate additional contributions of the ETS-family transcription factor ETV5 and the repressor RBPJ. In response to ERK signaling, ETV5 switches activity from supporting self-renewal and undergoes genome relocation linked to commissioning of enhancers activated in formative epiblast...
April 11, 2019: Cell Stem Cell
Julien Pontis, Evarist Planet, Sandra Offner, Priscilla Turelli, Julien Duc, Alexandre Coudray, Thorold W Theunissen, Rudolf Jaenisch, Didier Trono
Expansion of transposable elements (TEs) coincides with evolutionary shifts in gene expression. TEs frequently harbor binding sites for transcriptional regulators, thus enabling coordinated genome-wide activation of species- and context-specific gene expression programs, but such regulation must be balanced against their genotoxic potential. Here, we show that Krüppel-associated box (KRAB)-containing zinc finger proteins (KZFPs) control the timely and pleiotropic activation of TE-derived transcriptional cis regulators during early embryogenesis...
March 27, 2019: Cell Stem Cell
Etienne C E Wang, Zhenpeng Dai, Anthony W Ferrante, Charles G Drake, Angela M Christiano
Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining hair follicle stem cells (HFSCs) in a quiescent state. Here, we show that Oncostatin M (OSM), an IL-6 family cytokine, negatively regulates hair growth by signaling through JAK-STAT5 to maintain HFSC quiescence. Genetic deletion of the OSM receptor or STAT5 can induce premature HFSC activation, suggesting that the resting telogen stage is actively maintained by the hair follicle niche...
March 27, 2019: Cell Stem Cell
Xing Wei, Li Zhang, Zhicheng Zhou, Oh-Joon Kwon, Yiqun Zhang, Hoang Nguyen, Ruth Dumpit, Lawrence True, Peter Nelson, Baijun Dong, Wei Xue, Walter Birchmeier, Makoto M Taketo, Feng Xu, Chad J Creighton, Michael M Ittmann, Li Xin
Cell-autonomous Wnt signaling has well-characterized functions in controlling stem cell activity, including in the prostate. While niche cells secrete Wnt ligands, the effects of Wnt signaling in niche cells per se are less understood. Here, we show that stromal cells in the proximal prostatic duct near the urethra, a mouse prostate stem cell niche, not only produce multiple Wnt ligands but also exhibit strong Wnt/β-catenin activity. The non-canonical Wnt ligand Wnt5a, secreted by proximal stromal cells, directly inhibits proliefration of prostate epithelial stem or progenitor cells whereas stromal cell-autonomous canonical Wnt/β-catenin signaling indirectly suppresses prostate stem or progenitor activity via the transforming growth factor β (TGFβ) pathway...
March 26, 2019: Cell Stem Cell
Qinjie Weng, Jincheng Wang, Jiajia Wang, Danyang He, Zuolin Cheng, Feng Zhang, Ravinder Verma, Lingli Xu, Xinran Dong, Yunfei Liao, Xuelian He, Andrew Potter, Liguo Zhang, Chuntao Zhao, Mei Xin, Qian Zhou, Bruce J Aronow, Perry J Blackshear, Jeremy N Rich, Qiaojun He, Wenhao Zhou, Mario L Suvà, Ronald R Waclaw, S Steven Potter, Guoqiang Yu, Q Richard Lu
The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation...
March 23, 2019: Cell Stem Cell
Richard J Mills, Benjamin L Parker, Gregory A Quaife-Ryan, Holly K Voges, Elise J Needham, Aurelie Bornot, Mei Ding, Henrik Andersson, Magnus Polla, David A Elliott, Lauren Drowley, Maryam Clausen, Alleyn T Plowright, Ian P Barrett, Qing-Dong Wang, David E James, Enzo R Porrello, James E Hudson
We have previously developed a high-throughput bioengineered human cardiac organoid (hCO) platform, which provides functional contractile tissue with biological properties similar to native heart tissue, including mature, cell-cycle-arrested cardiomyocytes. In this study, we perform functional screening of 105 small molecules with pro-regenerative potential. Our findings reveal surprising discordance between our hCO system and traditional 2D assays. In addition, functional analyses uncovered detrimental effects of many hit compounds...
March 21, 2019: Cell Stem Cell
Ayesh K Seneviratne, Mingjing Xu, Juan J Aristizabal Henao, Val A Fajardo, Zhenyue Hao, Veronique Voisin, G Wei Xu, Rose Hurren, S Kim, Neil MacLean, Xiaoming Wang, Marcela Gronda, Danny Jeyaraju, Yulia Jitkova, Troy Ketela, Michael Mullokandov, David Sharon, Geethu Thomas, Raphaël Chouinard-Watkins, James R Hawley, Caitlin Schafer, Helen Loo Yau, Zaza Khuchua, Ahmed Aman, Rima Al-Awar, Atan Gross, Steven M Claypool, Richard Bazinet, Mathieu Lupien, Steven Chan, Daniel D De Carvalho, Mark D Minden, Gary D Bader, Ken D Stark, Paul LeBlanc, Aaron D Schimmer
Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling...
March 19, 2019: Cell Stem Cell
Puneet Agarwal, Stephan Isringhausen, Hui Li, Andrew J Paterson, Jianbo He, Álvaro Gomariz, Takashi Nagasawa, César Nombela-Arrieta, Ravi Bhatia
Chronic myeloid leukemia (CML) originates in a hematopoietic stem cell (HSC) transformed by the breakpoint cluster region (BCR)-abelson (ABL) oncogene and is effectively treated with tyrosine kinase inhibitors (TKIs). TKIs do not eliminate disease-propagating leukemic stem cells (LSCs), suggesting a deeper understanding of niche-dependent regulation of CML LSCs is required to eradicate disease. Cxcl12 is expressed in bone marrow niches and controls HSC maintenance, and here, we show that targeted deletion of Cxcl12 from mesenchymal stromal cells (MSCs) reduces normal HSC numbers but promotes LSC expansion by increasing self-renewing cell divisions, possibly through enhanced Ezh2 activity...
March 14, 2019: Cell Stem Cell
Carmen G Palii, Qian Cheng, Mark A Gillespie, Paul Shannon, Michalina Mazurczyk, Giorgio Napolitani, Nathan D Price, Jeffrey A Ranish, Edward Morrissey, Douglas R Higgs, Marjorie Brand
Hematopoiesis provides an accessible system for studying the principles underlying cell-fate decisions in stem cells. Proposed models of hematopoiesis suggest that quantitative changes in lineage-specific transcription factors (LS-TFs) underlie cell-fate decisions. However, evidence for such models is lacking as TF levels are typically measured via RNA expression rather than by analyzing temporal changes in protein abundance. Here, we used single-cell mass cytometry and absolute quantification by mass spectrometry to capture the temporal dynamics of TF protein expression in individual cells during human erythropoiesis...
March 14, 2019: Cell Stem Cell
Joe Z Zhang, Vittavat Termglinchan, Ning-Yi Shao, Ilanit Itzhaki, Chun Liu, Ning Ma, Lei Tian, Vicky Y Wang, Alex C Y Chang, Hongchao Guo, Tomoya Kitani, Haodi Wu, Chi Keung Lam, Kazuki Kodo, Nazish Sayed, Helen M Blau, Joseph C Wu
The diversity of cardiac lineages contributes to the heterogeneity of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). Here, we report the generation of a hiPSC TBX5Clover2 and NKX2-5TagRFP double reporter to delineate cardiac lineages and isolate lineage-specific subpopulations. Molecular analyses reveal that four different subpopulations can be isolated based on the differential expression of TBX5 and NKX2-5, TBX5+NKX2-5+, TBX5+NKX2-5-, TBX5-NKX2-5+, and TBX5-NKX2-5-, mimicking the first heart field, epicardial, second heart field, and endothelial lineages, respectively...
March 6, 2019: Cell Stem Cell
Lorna R Fiedler, Kathryn Chapman, Min Xie, Evie Maifoshie, Micaela Jenkins, Pelin Arabacilar Golforoush, Mohamed Bellahcene, Michela Noseda, Dörte Faust, Ashley Jarvis, Gary Newton, Marta Abreu Paiva, Mutsuo Harada, Daniel J Stuckey, Weihua Song, Josef Habib, Priyanka Narasimham, Rehan Aqil, Devika Sanmugalingam, Robert Yan, Lorenzo Pavanello, Motoaki Sano, Sam C Wang, Robert D Sampson, Sunthar Kanayaganam, George E Taffet, Lloyd H Michael, Mark L Entman, Tse-Hua Tan, Sian E Harding, Caroline M R Low, Catherine Tralau-Stewart, Trevor Perrior, Michael D Schneider
Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4...
March 1, 2019: Cell Stem Cell
Huaigeng Xu, Bo Wang, Miyuki Ono, Akihiro Kagita, Kaho Fujii, Noriko Sasakawa, Tatsuki Ueda, Peter Gee, Misato Nishikawa, Masaki Nomura, Fumiyo Kitaoka, Tomoko Takahashi, Keisuke Okita, Yoshinori Yoshida, Shin Kaneko, Akitsu Hotta
Induced pluripotent stem cells (iPSCs) have strong potential in regenerative medicine applications; however, immune rejection caused by HLA mismatching is a concern. B2M gene knockout and HLA-homozygous iPSC stocks can address this issue, but the former approach may induce NK cell activity and fail to present antigens, and it is challenging to recruit rare donors for the latter method. Here, we show two genome-editing strategies for making immunocompatible donor iPSCs. First, we generated HLA pseudo-homozygous iPSCs with allele-specific editing of HLA heterozygous iPSCs...
February 28, 2019: Cell Stem Cell
Joel Johansson, Mate Naszai, Michael C Hodder, Karen A Pickering, Bryan W Miller, Rachel A Ridgway, Yachuan Yu, Pascal Peschard, Saskia Brachmann, Andrew D Campbell, Julia B Cordero, Owen J Sansom
Ral GTPases are RAS effector molecules and by implication a potential therapeutic target for RAS mutant cancer. However, very little is known about their roles in stem cells and tissue homeostasis. Using Drosophila, we identified expression of RalA in intestinal stem cells (ISCs) and progenitor cells of the fly midgut. RalA was required within ISCs for efficient regeneration downstream of Wnt signaling. Within the murine intestine, genetic deletion of either mammalian ortholog, Rala or Ralb, reduced ISC function and Lgr5 positivity, drove hypersensitivity to Wnt inhibition, and impaired tissue regeneration following damage...
February 28, 2019: Cell Stem Cell
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