scholarly journals Wnt-and Glutamate-receptors orchestrate stem cell dynamics and asymmetric cell division

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sergi Junyent ◽  
Joshua C Reeves ◽  
James LA Szczerkowski1 ◽  
Clare L Garcin ◽  
Tung-Jui Trieu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Glutamate Receptors ◽  
Cell Fate ◽  
Cell Biology ◽  
Wnt Pathway ◽  
Asymmetric Cell Division ◽  
Cell Signalling ◽  
Embryonic Stem ◽  
Kainate Receptors

The Wnt-pathway is part of a signalling network that regulates many aspects of cell biology. Recently we discovered crosstalk between AMPA/Kainate-type ionotropic glutamate receptors (iGluRs) and the Wnt-pathway during the initial Wnt3a-interaction at the cytonemes of mouse embryonic stem cells (ESCs). Here, we demonstrate that this crosstalk persists throughout the Wnt3a-response in ESCs. Both AMPA- and Kainate-receptors regulate early Wnt3a-recruitment, dynamics on the cell membrane, and orientation of the spindle towards a Wnt3a-source at mitosis. AMPA-receptors specifically are required for segregating cell fate components during Wnt3a-mediated asymmetric cell division (ACD). Using Wnt-pathway component knockout lines, we determine that Wnt co-receptor Lrp6 has particular functionality over Lrp5 in cytoneme formation, and in facilitating ACD. Both Lrp5 and 6, alongside pathway effector β-catenin act in concert to mediate the positioning of the dynamic interaction with, and spindle orientation to, a localized Wnt3a-source. Wnt-iGluR crosstalk may prove pervasive throughout embryonic and adult stem cell signalling.

scholarly journals Wnt- and Glutamate-receptors orchestrate stem cell dynamics and asymmetric cell division

2020 ◽  
Author(s):  
Sergi Junyent ◽  
Joshua Reeves ◽  
James L. A. Szczerkowski ◽  
Clare L. Garcin ◽  
Tung-Jui Trieu ◽  
...  
Keyword(s):  
Cell Division ◽  
Cell Fate ◽  
Cell Biology ◽  
Wnt Pathway ◽  
Asymmetric Cell Division ◽  
Embryonic Stem ◽  
Cell Dynamics ◽  
Pathway Activation ◽  
Wnt Ligands ◽  
Ligand Stabilization

ABSTRACTWnt signalling regulates many aspects of cell biology. Wnt-pathway activation and its downstream effects have been extensively studied, but the dynamic analysis of Wnt-ligands on mammalian cellular membranes is obstructed by difficulties of visualization. We overcome this using microbead-tethered Wnts presented to single embryonic stem cells, which undergo Wnt-mediated asymmetric cell division (ACD). Through live imaging and genetic editing, we show that knockout of Wnt co-receptor Lrp5 promotes cytoneme formation and Wnt-recruitment, which requires Lrp6 and β-catenin. Lrp5 facilitates ligand-retention at the membrane, and alongside Lrp6 mediates Wnt-ligand stabilization and positioning. β-catenin or Wnt co-receptor knockout causes misorientation at mitosis, and all but Lrp5 are required for Wnt-orientated ACD. Surprisingly, ionotropic glutamate receptor (iGluR) activity enables initial Wnt-recruitment, positioning, and ultimately oriented ACD. Uniquely, we have scrutinized the early Wnt ligand-membrane interaction, linking roles of Wnt-pathway components and crosstalk with iGluRs in guiding cell fate determination by oriented ACD.

Asymmetric organelle inheritance predicts human blood stem cell fate

Blood ◽  
2021 ◽  
Author(s):  
Dirk Loeffler ◽  
Florin Schneiter ◽  
Weijia Wang ◽  
Arne Wehling ◽  
Tobias Kull ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Human Blood ◽  
Asymmetric Cell Division ◽  
Cell Fates ◽  
Hematopoietic Stem ◽  
Stem Cell Fate ◽  
Blood Stem Cells

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

Strontium regulates stem cell fate during osteogenic differentiation through asymmetric cell division

2021 ◽  
Vol 119 ◽  
pp. 432-443
Author(s):  
Yanqun Li ◽  
Jianhui Yue ◽  
Yuan Liu ◽  
Jun Wu ◽  
Min Guan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Osteogenic Differentiation ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Stem Cell Fate

scholarly journals Metabolic determinants of embryonic development and stem cell fate

2015 ◽  
Vol 27 (1) ◽  
pp. 82 ◽  
Author(s):  
Clifford D. L. Folmes ◽  
Andre Terzic
Keyword(s):  
Stem Cell ◽  
Energy Metabolism ◽  
Cell Fate ◽  
Epigenetic Regulation ◽  
Cell Biology ◽  
Metabolic Flux ◽  
Cell Metabolism ◽  
Cell Signalling ◽  
Regulation Of Gene Expression ◽  
Stem Cell Differentiation

Decoding stem cell metabolism has implicated a tight linkage between energy metabolism and cell fate regulation, a dynamic interplay vital in the execution of developmental and differentiation programs. The inherent plasticity in energy metabolism enables prioritisation of metabolic pathways in support of stage-specific demands. Beyond traditional support of energetic needs, intermediate metabolism may also dictate cell fate choices through regulation of cellular signalling and epigenetic regulation of gene expression. The notion of a ‘metabolism-centric’ control of stem cell differentiation has been informed by developmental embryogenesis based upon an on-demand paradigm paramount in defining diverse developmental behaviours, from a post-fertilisation nascent zygote to complex organogenesis leading to adequate tissue formation and maturation. Monitored through natural or bioengineered stem cell surrogates, nutrient-responsive metabolites are identified as mediators of cross-talk between metabolic flux, cell signalling and epigenetic regulation charting, collectively, whether a cell will self-renew to maintain progenitor pools, lineage specify to ensure tissue (re)generation or remain quiescent to curb stress damage. Thus, bioenergetics are increasingly recognised as integral in governing stemness and associated organogenic decisions, paving the way for metabolism-defined targets in control of embryology, stem cell biology and tissue regeneration.

The Significant Role of Centrosomes in Stem Cell Division and Differentiation

2011 ◽  
Vol 17 (4) ◽  
pp. 506-512 ◽  
Author(s):  
Heide Schatten ◽  
Qing-Yuan Sun
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Primary Cilia ◽  
Asymmetric Cell Division ◽  
Embryonic Stem ◽  
Stem Cell Maintenance ◽  
Tissue Repair And Regeneration ◽  
Mother And Daughter ◽  
Stem Cell Division

AbstractThe role of centrosomes in stem cell division has recently been highlighted and further ascribes important functions to centrosomes in stem cell maintenance, cellular differentiation, and development. Advanced cell and molecular studies coupled with immunofluorescence, electron microscopy, and live cell imaging of specific centrosome proteins have contributed greatly to our knowledge of centrosome composition, structure, and dynamics and have uncovered new insights into mechanisms of centrosome functions in asymmetric cell division. The establishment of asymmetry and differential positioning of mother and daughter centrosomes during stem cell mitosis is important for allowing one cell to maintain stem cell characteristics while the sibling cell undergoes differentiation. Another key role for centrosomes has been revealed in primary cilia of embryonic stem cells that play significant roles in cellular signaling and are therefore critically important for stem cell decisions. Studies of signaling through primary cilia may contribute important information that may aid in the production of specific cells that are suitable for tissue repair and regeneration in the field of regenerative medicine.

scholarly journals The Stem Cell Division Theory of Cancer

2017 ◽  
Author(s):  
Miguel López-Lázaro
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Cell Biology ◽  
Cancer Registries ◽  
Cell Divisions ◽  
Division Process ◽  
Dna Alterations ◽  
Cellular Components

All cancer registries constantly show striking differences in cancer incidence by age and among tissues. For example, lung cancer is diagnosed hundreds of times more often at age 70 than at age 20, and this cancer in nonsmokers occurs thousands of times more frequently than heart cancer in smokers. An analysis of these differences using basic concepts in cell biology indicates that cancer is the end-result of the accumulation of cell divisions in stem cells. In other words, the main determinant of carcinogenesis is the number of cell divisions that the DNA of a stem cell has accumulated in any type of cell from the zygote. Cell division, process by which a cell copies and separates its cellular components to finally split into two cells, is necessary to produce the large number of cells required for living. However, cell division can lead to a variety of cancer-promoting errors, such as mutations occurring during DNA replication, chromosome aberrations arising during mitosis, errors in the distribution of cell-fate determinants between the daughter cells, and failures to restore physical interactions with other tissue components. Some of these errors are spontaneous, others are promoted by endogenous DNA damage occurring during quiescence, and others are influenced by pathological and environmental factors. The cell divisions required for carcinogenesis are primarily caused by multiple local and systemic physiological signals rather than by errors in the DNA of the cells. As carcinogenesis progresses, the accumulation of DNA errors promotes cell division and eventually triggers cell division under permissive extracellular environments. The accumulation of cell divisions in stem cells drives not only the accumulation of the DNA alterations required for carcinogenesis, but also the formation and growth of the abnormal cell populations that characterize the disease. This model of carcinogenesis provides a new framework for understanding the disease and has important implications for cancer prevention and therapy.

scholarly journals Abscission Couples Cell Division to Embryonic Stem Cell Fate

2020 ◽  
Vol 55 (2) ◽  
pp. 195-208.e5
Author(s):  
Agathe Chaigne ◽  
Céline Labouesse ◽  
Ian J. White ◽  
Meghan Agnew ◽  
Edouard Hannezo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Embryonic Stem Cell ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Stem Cell Fate

scholarly journals Vitamin C in Stem Cell Biology: Impact on Extracellular Matrix Homeostasis and Epigenetics

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Cristina D'Aniello ◽  
Federica Cermola ◽  
Eduardo Jorge Patriarca ◽  
Gabriella Minchiotti
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Stem Cell ◽  
Vitamin C ◽  
Cell Fate ◽  
Cell Biology ◽  
Embryonic Stem ◽  
Redox Status ◽  
Stem Cell Biology ◽  
Prolyl Hydroxylases

Transcription factors and signaling molecules are well-known regulators of stem cell identity and behavior; however, increasing evidence indicates that environmental cues contribute to this complex network of stimuli, acting as crucial determinants of stem cell fate.L-Ascorbic acid (vitamin C (VitC)) has gained growing interest for its multiple functions and mechanisms of action, contributing to the homeostasis of normal tissues and organs as well as to tissue regeneration. Here, we review the main functions of VitC and its effects on stem cells, focusing on its activity as cofactor of Fe+2/αKG dioxygenases, which regulate the epigenetic signatures, the redox status, and the extracellular matrix (ECM) composition, depending on the enzymes’ subcellular localization. Acting as cofactor of collagen prolyl hydroxylases in the endoplasmic reticulum, VitC regulates ECM/collagen homeostasis and plays a key role in the differentiation of mesenchymal stem cells towards osteoblasts, chondrocytes, and tendons. In the nucleus, VitC enhances the activity of DNA and histone demethylases, improving somatic cell reprogramming and pushing embryonic stem cell towards the naive pluripotent state. The broad spectrum of actions of VitC highlights its relevance for stem cell biology in both physiology and disease.

scholarly journals Ankle2, A Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway

2019 ◽  
Author(s):  
N. Link ◽  
H. Chung ◽  
A. Jolly ◽  
M. Withers ◽  
B. Tepe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Nuclear Envelope ◽  
Cell Fate ◽  
Zika Virus ◽  
Asymmetric Cell Division ◽  
Brain Size ◽  
Stem Cell Division ◽  
Fate Determinants ◽  
Cell Fate Determinants

ABSTRACTNeuroblasts in flies divide asymmetrically by establishing polarity, distributing cell fate determinants asymmetrically, and positioning their spindle for cell division. The apical complex contains aPKC, Bazooka (Par3), and Par6, and its activity depends on L(2)gl. We show that Ankle2 interacts with L(2)gl and affects aPKC. Reducing Ankle2 levels disrupts ER and nuclear envelope morphology, releasing the kinase Ballchen/VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par complex localization, and spindle alignment defects. Importantly, removal of one copy ofballchen/VRK1orl(2)glsuppresses the loss ofAnkle2and restores viability and brain size. The Zika virus NS4A protein interacts withDrosophilaAnkle2 and VRK1 in dividing neuroblasts. Human mutational studies implicate this neural cell division pathway in microcephaly and motor neuron disease. In summary, NS4A, ANKLE2, VRK1 and LLGL1 define a novel pathway that impinges on asymmetric determinants of neural stem cell division.

scholarly journals Breaking symmetry: the asymmetries in epigenetic inheritance

2021 ◽  
Vol 43 (1) ◽  
pp. 14-19
Author(s):  
Emily Zion ◽  
Xin Chen
Keyword(s):  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Genetic Information ◽  
Asymmetric Cell Division ◽  
Epigenetic Inheritance ◽  
Multicellular Organism ◽  
Epigenetic Information ◽  
Distinct Cell ◽  
Stem Cell Division

Symmetry and asymmetry are the fundamental aspects of life. Most cells within a multicellular organism contain the same genetic information, passed on from one originating cell, the zygote; however, these cells can take on a variety of different identities, with diverse appearances and functions. A fundamental question in biology ponders how cells containing identical DNA content can take on different cell identities. Epigenetic mechanisms could be the symmetry-breaking factor, as they are able to change the gene expression in cells without changing the DNA sequence. While the process of duplication and segregation of DNA during cell division has been well studied, it is less understood how the epigenetic information is established and inherited in the cells within a multicellular organism. Studies of asymmetric stem cell division, where a stem cell division gives rise to a self-renewed stem cell and a differentiating daughter cell, provide a model to study how epigenetic information is maintained or changed to produce daughter cells with identical genetic information but distinct cell fates. Here, we discuss the findings and ideas of how epigenetic information is maintained or changed during asymmetric cell division and the importance of this asymmetry in influencing cell fate.

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