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Stem Cell Reports

Ashlee M Strubberg, Daniel A Veronese Paniagua, Tingting Zhao, Leeran Dublin, Thomas Pritchard, Peter O Bayguinov, James A J Fitzpatrick, Blair B Madison
Intestinal epithelial stem cell (IESC) fate is promoted by two major transcriptional regulators, the TCF4/β-catenin complex and ASCL2, which drive expression of IESC-specific factors, including Lgr5, Ephb2, and Rnf43. Canonical Wnt signaling via TCF4/β-catenin directly transactivates Ascl2, which in turn auto-regulates its own expression. Conversely, Let-7 microRNAs antagonize the IESC lineage by repressing specific mRNA targets. Here, we identify the zinc finger transcription factor PLAGL2 as a Let-7 target that regulates IESC fate...
July 9, 2018: Stem Cell Reports
Antonio Morales-Hernández, Alice Martinat, Ashley Chabot, Guolian Kang, Shannon McKinney-Freeman
C57BL/6N (N) and C57BL/6J (J) mice possess key genetic differences, including a deletion in the Nicotinamide nucleotide transhydrogenase (Nnt) gene that results in a non-functional protein in J mice. NNT regulates mitochondrial oxidative stress. Although elevated oxidative stress can compromise hematopoietic stem and progenitor cell (HSPC) function, it is unknown whether N- and J-HSPCs are functionally equivalent. Here, we report that J-HSPCs display compromised short-term hematopoietic repopulating activity relative to N-HSPCs that is defined by a delay in lymphoid reconstitution and impaired function of specific multi-potent progenitor populations post transplant...
July 6, 2018: Stem Cell Reports
Zeyidan Jiapaer, Guoping Li, Dan Ye, Mingliang Bai, Jianguo Li, Xudong Guo, Yanhua Du, Dingwen Su, Wenwen Jia, Wen Chen, Guiying Wang, Yangyang Yu, Fugui Zhu, Xiaoping Wan, Jiuhong Kang
Although the functional roles of long noncoding RNAs (lncRNAs) have been increasingly identified, few lncRNAs that control the naïve state of embryonic stem cells (ESCs) are known. Here, we report a naïve-state-associated lncRNA, LincU, which is intrinsically activated by Nanog in mESCs. LincU-deficient mESCs exhibit a primed-like pluripotent state and potentiate the transition from the naïve state to the primed state, whereas ectopic LincU expression maintains mESCs in the naïve state. Mechanistically, we demonstrate that LincU binds and stabilizes the DUSP9 protein, an ERK-specific phosphatase, and then constitutively inhibits the ERK1/2 signaling pathway, which critically contributes to maintenance of the naïve state...
July 4, 2018: Stem Cell Reports
Xinglong Yang, Jianlong Zhou, Jingjin He, Jingfeng Liu, Hui Wang, Yachen Liu, Tao Jiang, Qianbing Zhang, Xuemei Fu, Yang Xu
Due to its lack of both innate and acquired immune responses to human cells, the NODSCIDIl2rγ-/- (NSG) mouse model has become an important tool for human stem cell research. When compared with the mouse, the rat is physiologically more similar to humans and offers advantages in preclinical efficacy studies on human stem cells, particularly in evaluating neural, hepatic, and cardiac functions. Therefore, we generated a human SIRPα+ Prdkc-/- Il2rγ-/- rat model, denoted NSG-like (NSGL) rat, which expresses human SIRPα and is abolished in the development of B, T, and natural killer cells...
June 29, 2018: Stem Cell Reports
Kenji Kubara, Kazuto Yamazaki, Yasuharu Ishihara, Takuya Naruto, Huan-Ting Lin, Ken Nishimura, Manami Ohtaka, Mahito Nakanishi, Masashi Ito, Kappei Tsukahara, Tomohiro Morio, Masatoshi Takagi, Makoto Otsu
Oncogenic KRAS mutations in hematopoietic stem cells cause RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). KRAS plays essential roles in stemness maintenance in some types of stem cells. However, its roles in pluripotent stem cells (PSCs) are poorly understood. Here, we investigated the roles of KRAS on stemness in the context of induced PSCs (iPSCs). We used KRAS mutant (G13C/WT) and wild-type isogenic (WT/WT) iPSCs from the same RALD patients, as well as wild-type (WTed /WT) and heterozygous knockout (Δed /WT) iPSCs, both obtained by genome editing from the same G13C/WT clone...
June 28, 2018: Stem Cell Reports
Baarkullah Awan, David Turkov, Cameron Schumacher, Antonio Jacobo, Amber McEnerney, Ashley Ramsey, Gege Xu, Dayoung Park, Stefanos Kalomoiris, Wei Yao, Li-En Jao, Miguel L Allende, Carlito B Lebrilla, Fernando A Fierro
Since hundreds of clinical trials are investigating the use of multipotent stromal cells (MSCs) for therapeutic purposes, effective delivery of the cells to target tissues is critical. We have found an unexplored mechanism, by which basic fibroblast growth factor (FGF2) induces expression of fucosyltransferase 8 (FUT8) to increase core fucosylations of N-linked glycans of membrane-associated proteins, including several integrin subunits. Gain- and loss-of-function experiments show that FUT8 is both necessary and sufficient to induce migration of MSCs...
June 28, 2018: Stem Cell Reports
Lise Morizur, Alexandra Chicheportiche, Laurent R Gauthier, Mathieu Daynac, François D Boussin, Marc-André Mouthon
Deciphering the mechanisms that regulate the quiescence of adult neural stem cells (NSCs) is crucial for the development of therapeutic strategies based on the stimulation of their endogenous regenerative potential in the damaged brain. We show that LeXbright cells sorted from the adult mouse subventricular zone exhibit all the characteristic features of quiescent NSCs. Indeed, they constitute a subpopulation of slowly dividing cells that is able to enter the cell cycle to regenerate the irradiated niche. Comparative transcriptomic analyses showed that they express hallmarks of NSCs but display a distinct molecular signature from activated NSCs (LeX+ EGFR+ cells)...
June 27, 2018: Stem Cell Reports
Jianshe Lang, Yichen Cheng, Alyssa Rolfe, Christy Hammack, Daniel Vera, Kathleen Kyle, Jingying Wang, Torsten B Meissner, Yi Ren, Chad Cowan, Hengli Tang
Zika virus (ZIKV) and dengue virus (DENV) are two closely related flaviviruses that lead to different clinical outcomes. The mechanism for the distinct pathogenesis of ZIKV and DENV is poorly understood. Here, we investigate ZIKV and DENV infection of macrophages using a human pluripotent stem cell (hPSC)-derived macrophage model and discover key virus-specific responses. ZIKV and DENV productively infect hPSC-derived macrophages. DENV, but not ZIKV, infection of macrophages strongly activates macrophage migration inhibitory factor (MIF) secretion and decreases macrophage migration...
June 27, 2018: Stem Cell Reports
Scott Bell, Gilles Maussion, Malvin Jefri, Huashan Peng, Jean-Francois Theroux, Heika Silveira, Vincent Soubannier, Hanrong Wu, Peng Hu, Ekaterina Galat, S Gabriela Torres-Platas, Camille Boudreau-Pinsonneault, Liam A O'Leary, Vasiliy Galat, Gustavo Turecki, Thomas M Durcan, Edward A Fon, Naguib Mechawar, Carl Ernst
Heterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment. We developed clonal models of GRIN2B deletion and loss-of-function mutations in a region coding for the glutamate binding domain in human cells and generated neurons from a patient harboring a missense mutation in the same domain. Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation, a result supported by extensive protein analyses...
June 15, 2018: Stem Cell Reports
Maria Rostovskaya, Samantha Donsante, Benedetto Sacchetti, Dimitra Alexopoulou, Sylvia Klemroth, Andreas Dahl, Mara Riminucci, Paolo Bianco, Konstantinos Anastassiadis
Bone, cartilage, and marrow adipocytes are generated by skeletal progenitors, but the relationships between lineages and mechanisms controlling their differentiation are poorly understood. We established mouse clonal skeletal progenitors with distinct differentiation properties and analyzed their transcriptome. Unipotent osteogenic and adipogenic cells expressed specific transcriptional programs, whereas bipotent clones combined expression of those genes and did not show a unique signature. We tested potential regulators of lineage commitment and found that in the presence of interferon-γ (IFNγ) adipogenic clones can be induced to osteogenesis and that their adipogenic capacity is inhibited...
June 14, 2018: Stem Cell Reports
Xiaofang Wang, Fang Dong, Sen Zhang, Wanzhu Yang, Wenying Yu, Zhao Wang, Shanshan Zhang, Jinhong Wang, Shihui Ma, Peng Wu, Yun Gao, Ji Dong, Fuchou Tang, Tao Cheng, Hideo Ema
Transforming growth factor β1 (TGF-β1) plays a role in the maintenance of quiescent hematopoietic stem cells (HSCs) in vivo. We asked whether TGF-β1 controls the cell cycle status of HSCs in vitro to enhance the reconstitution activity. To examine the effect of TGF-β1 on the HSC function, we used an in vitro culture system in which single HSCs divide with the retention of their short- and long-term reconstitution ability. Extensive single-cell analyses showed that, regardless of its concentration, TGF-β1 slowed down the cell cycle progression of HSCs but consequently suppressed their self-renewal potential...
June 14, 2018: Stem Cell Reports
Yu-Feng Liu, Shao-Ying Zhang, Ying-Ying Chen, Kun Shi, Bin Zou, Jun Liu, Qiong Yang, Hua Jiang, Lai Wei, Chang-Zheng Li, Meng Zhao, Dmitry I Gabrilovich, Hui Zhang, Jie Zhou
The bone marrow niche plays a critical role in controlling the fate of hematopoietic stem cells (HSCs) by integrating intrinsic and extrinsic signals. However, the molecular events in the HSC niche remain to be investigated. Here, we report that intercellular adhesion molecule-1 (ICAM-1) maintains HSC quiescence and repopulation capacity in the niche. ICAM-1-deficient mice (ICAM-1-/- ) displayed significant expansion of phenotypic long-term HSCs with impaired quiescence, as well as favoring myeloid cell expansion...
June 14, 2018: Stem Cell Reports
Gat Rauner, Tania Kudinov, Shlomit Gilad, Gil Hornung, Itamar Barash
Aiming to unravel the top of the mammary epithelial cell hierarchy, a subset of the CD49fhigh CD24med mammary repopulating units (MRUs) was identified by flow cytometry, expressing high levels of CD200 and its receptor CD200R1. These MRUCD200/CD200R1 repopulated a larger area of de-epithelized mammary fat pads than the rest of the MRUs, termed MRUnot CD200/CD200R1 . MRUCD200/CD200R1 maintained a much lower number of divergently defined, highly expressed genes and pathways that support better cell growth, development, differentiation, and progenitor activity than their MRUnot CD200/CD200R1 counterparts...
June 14, 2018: Stem Cell Reports
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 expression. However, it is so far unclear whether 2i acts through an inductive or selective mechanism. Here, we use continuous time-lapse imaging to quantify the dynamics of death, proliferation, and Nanog expression in mouse ESCs after 2i addition...
May 10, 2018: Stem Cell Reports
Chang Liu, Ran Wang, Zhisong He, Pierre Osteil, Emilie Wilkie, Xianfa Yang, Jun Chen, Guizhong Cui, Wenke Guo, Yingying Chen, Guangdun Peng, Patrick P L Tam, Naihe Jing
The molecular mechanism underpinning the specification of the ectoderm, a transient germ-layer tissue, during mouse gastrulation was examined here in a stem cell-based model. We captured a self-renewing cell population with enhanced ectoderm potency from mouse epiblast stem cells (EpiSCs) by suppressing Nodal signaling activity. The transcriptome of the Nodal-inhibited EpiSCs resembles that of the anterior epiblast of embryonic day (E)7.0 and E7.5 mouse embryo, which is accompanied by chromatin modifications that reflect the priming of ectoderm lineage-related genes for expression...
July 10, 2018: Stem Cell Reports
Ismail Osman, Jun Wei Pek
Animal reproduction responds to nutritional status. During starvation, Drosophila and Caenorhabditis elegans enter a period of reproductive diapause with increase apoptosis, while maintaining a stable pool of germline stem cells (GSCs). How GSCs are protected is not understood. Here, we show that a sisRNA/miRNA axis maintains ovarian GSCs during starvation in Drosophila. Starvation induces the expression of an ovary-enriched sisRNA sisR-2, which negatively regulates GSC maintenance via a fatty acid metabolism gene dFAR1...
July 10, 2018: Stem Cell Reports
Katherine C Michelis, Aya Nomura-Kitabayashi, Laura Lecce, Oscar Franzén, Simon Koplev, Yang Xu, Maria Paola Santini, Valentina D'Escamard, Jonathan T L Lee, Valentin Fuster, Roger Hajjar, Ramachandra C Reddy, Joanna Chikwe, Paul Stelzer, Farzan Filsoufi, Allan Stewart, Anelechi Anyanwu, Johan L M Björkegren, Jason C Kovacic
Mesenchymal stem cells (MSCs) reportedly exist in a vascular niche occupying the outer adventitial layer. However, these cells have not been well characterized in vivo in medium- and large-sized arteries in humans, and their potential pathological role is unknown. To address this, healthy and diseased arterial tissues were obtained as surplus surgical specimens and freshly processed. We identified that CD90 marks a rare adventitial population that co-expresses MSC markers including PDGFRα, CD44, CD73, and CD105...
July 10, 2018: Stem Cell Reports
Takashi Iezaki, Tetsuhiro Horie, Kazuya Fukasawa, Makoto Kitabatake, Yuka Nakamura, Gyujin Park, Yuki Onishi, Kakeru Ozaki, Takashi Kanayama, Manami Hiraiwa, Yuka Kitaguchi, Katsuyuki Kaneda, Takayuki Manabe, Yasuhito Ishigaki, Mutsuhito Ohno, Eiichi Hinoi
The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) regulates cellular function in various cell types. Although the role of mTORC1 in skeletogenesis has been investigated previously, here we show a critical role of mTORC1/4E-BPs/SOX9 axis in regulating skeletogenesis through its expression in undifferentiated mesenchymal cells. Inactivation of Raptor, a component of mTORC1, in limb buds before mesenchymal condensations resulted in a marked loss of both cartilage and bone. Mechanistically, we demonstrated that mTORC1 selectively controls the RNA translation of Sox9, which harbors a 5' terminal oligopyrimidine tract motif, via inhibition of the 4E-BPs...
July 10, 2018: Stem Cell Reports
Leqian Yu, Junjun Li, Jiayin Hong, Yasuhiro Takashima, Nanae Fujimoto, Minako Nakajima, Akihisa Yamamoto, Xiaofeng Dong, Yujiao Dang, Yu Hou, Wei Yang, Itsunari Minami, Keisuke Okita, Motomu Tanaka, Chunxiong Luo, Fuchou Tang, Yong Chen, Chao Tang, Hidetoshi Kotera, Li Liu
We show that a human pluripotent stem cell (hPSC) population cultured on a low-adhesion substrate developed two hPSC subtypes with different colony morphologies: flat and domed. Notably, the dome-like cells showed higher active proliferation capacity and increased several pluripotent genes' expression compared with the flat monolayer cells. We further demonstrated that cell-matrix adhesion mediates the interaction between cell morphology and expression of KLF4 and KLF5 through a serum response factor (SRF)-based regulatory double loop...
July 10, 2018: Stem Cell Reports
Pablo Navarro
In this issue of Stem Cell Reports, Hastreiter et al. (2018) use continuous time-lapse imaging of mouse embryonic stem cells to investigate how the inhibition of GSK3b and MEK/ERK (2i) leads to homogeneous expression of the transcription factor Nanog. They show that both induction of Nanog expression and selection against cells expressing low levels of Nanog contribute to the homogeneous appearance of 2i cultures.
July 10, 2018: Stem Cell Reports
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