Membrane tension regulated mechanotransduction drives fate transitions in embryonic stem cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE159433 | GEO | 2020/10/14
REPOSITORIES: GEO
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Project description:Plasma membrane tension is an important feature that determines the cell shape and influences processes such as cell motility, spreading, endocytosis and exocytosis. Unconventional class 1 myosins are potent regulators of plasma membrane tension because they physically link the plasma membrane with the adjacent cytoskeleton. We identified nuclear myosin 1 (NM1) - a putative nuclear isoform of myosin 1c (Myo1c) - as a new player in the field. Although having specific nuclear function, we show that NM1 localizes preferentially to the plasma membrane. Deletion of NM1 causes more than 50% increase in the elasticity of the plasma membrane around the actin cytoskeleton as measured by atomic force microscopy. This higher elasticity of NM1 knock-out cells leads to 25% higher resistance to short-term hypotonic environment and rapid cell swelling. In contrary, overexpression of NM1 in WT cells leads to additional 30% reduction of their survival. We have brought evidence that NM1 has a direct functional role in the cytoplasm as a dynamic linker between the cell membrane and the underlying cytoskeleton, regulating the degree of effective plasma membrane tension. We used tissues from NM1 WT and KO mice with highest expression of NM1, lungs and heart (3 replicates each) and skin fibroblast derived from each mice (2 replicates each)
2015-12-05 | E-GEOD-75709 | biostudies-arrayexpress
Project description:Plasma membrane tension is an important feature that determines the cell shape and influences processes such as cell motility, spreading, endocytosis and exocytosis. Unconventional class 1 myosins are potent regulators of plasma membrane tension because they physically link the plasma membrane with the adjacent cytoskeleton. We identified nuclear myosin 1 (NM1) - a putative nuclear isoform of myosin 1c (Myo1c) - as a new player in the field. Although having specific nuclear function, we show that NM1 localizes preferentially to the plasma membrane. Deletion of NM1 causes more than 50% increase in the elasticity of the plasma membrane around the actin cytoskeleton as measured by atomic force microscopy. This higher elasticity of NM1 knock-out cells leads to 25% higher resistance to short-term hypotonic environment and rapid cell swelling. In contrary, overexpression of NM1 in WT cells leads to additional 30% reduction of their survival. We have brought evidence that NM1 has a direct functional role in the cytoplasm as a dynamic linker between the cell membrane and the underlying cytoskeleton, regulating the degree of effective plasma membrane tension.
2015-12-05 | GSE75709 | GEO
Project description:Hypoxia augments human embryonic stem cell self-renewal via hypoxia-inducible factor 2M-NM-1 (HIF2M-NM-1) activated OCT4 (POU5F1) transcription. Hypoxia also increases the efficiency of reprogramming differentiated cells to a pluripotent-like state. Combined, these findings suggest that low oxygen (O2) tension would impair the purposeful differentiation of pluripotent stem cells. Here, we show that low O2 tension and HIF activity instead promotes appropriate hESC differentiation. Through gain and loss of function studies, we implicate O2 tension as a modifier of a key cell fate decision, namely whether neural progenitors differentiate towards neurons or glia. Furthermore, our data show that even transient changes in O2 concentration can affect cell fate through HIF by regulating the activity of MYC, a regulator of LIN28/let-7 that is critical for fate decisions in the neural lineage. We also identify key small molecules that can take advantage of this pathway to quickly and efficiently promote the development of mature cell types. We used microarrays to detail the global gene expression of human neural progenitor cells (NPC) cultured in physiological (2%) oxygen tension. By comparing NPCs with activated Hypoxia inducible factor (HIF) activity (DFX treatment) and NPCs with diminished HIF activity (HIF1M-NM-2 knockdown), we identified genes that are important for NPC fate decision under physiological oxygen concentration. We also used microarrays to obtain a global gene expression profiling during embryoid bodies formation using ES cells with diminished HIF activity. In HIF activation experiments, two ES lines and one iPS line-derived NPC were used, with or without DFX treatment for 5 days. In HIF1M-NM-2 knockdown experiments, NPCs were derived from either shHIF1M-NM-2 or control ES lines. In embryoid body formation experiments, day0 (ES stage) and day6 EBs were generated from either shHIF1M-NM-2 or control ES lines in 2% oxygen.
2014-09-30 | E-GEOD-61842 | biostudies-arrayexpress
Project description:Patient-derived organoids and cellular spheroids recapitulate tissue physiology with remarkable fidelity. We investigated how engagement with a reconstituted basement membrane (rBM) in three dimensions (3D) supports the polarized, stress resilient tissue phenotype of mammary epithelial spheroids. Cells interacting with rBM in 3D had reduced levels of total and actin-associated filamin and decreased cortical actin tension that increased plasma membrane protrusions to promote negative plasma membrane curvature and plasma membrane protein associations linked to protein secretion. By contrast, cells engaging rBM in 2D had high cortical actin tension that forced filamin unfolding and endoplasmic reticulum (ER) associations. Enhanced filamin-ER interactions increased levels of PKR-like ER kinase effectors and ER-plasma membrane contact sites that compromised calcium homeostasis and diminished cell viability. Consequently, cells with low cortical actin tension had reduced ER stress and survived better. Consistently, cortical actin tension in cellular spheroids regulated polarized BM membrane deposition and sensitivity to exogenous stress. The findings implicate cortical actin tension-mediated filamin unfolding in ER function, and underscore the importance of tissue mechanics in organoid homeostasis.
2022-06-08 | GSE150695 | GEO
Project description:Hypoxia augments human embryonic stem cell self-renewal via hypoxia-inducible factor 2α (HIF2α) activated OCT4 (POU5F1) transcription. Hypoxia also increases the efficiency of reprogramming differentiated cells to a pluripotent-like state. Combined, these findings suggest that low oxygen (O2) tension would impair the purposeful differentiation of pluripotent stem cells. Here, we show that low O2 tension and HIF activity instead promotes appropriate hESC differentiation. Through gain and loss of function studies, we implicate O2 tension as a modifier of a key cell fate decision, namely whether neural progenitors differentiate towards neurons or glia. Furthermore, our data show that even transient changes in O2 concentration can affect cell fate through HIF by regulating the activity of MYC, a regulator of LIN28/let-7 that is critical for fate decisions in the neural lineage. We also identify key small molecules that can take advantage of this pathway to quickly and efficiently promote the development of mature cell types. We used microarrays to detail the global gene expression of human neural progenitor cells (NPC) cultured in physiological (2%) oxygen tension. By comparing NPCs with activated Hypoxia inducible factor (HIF) activity (DFX treatment) and NPCs with diminished HIF activity (HIF1β knockdown), we identified genes that are important for NPC fate decision under physiological oxygen concentration. We also used microarrays to obtain a global gene expression profiling during embryoid bodies formation using ES cells with diminished HIF activity.
2014-09-30 | GSE61842 | GEO
Project description:Clathrin-mediated endocytosis is an essential cellular internalisation pathway involving the dynamic assembly of clathrin and accessory proteins to form membrane-bound vesicles. The evolutionarily ancient TSET/TPLATE complex (TPC) plays an essential, but not well-defined role in endocytosis in plants. Here, we show that two highly disordered TPC subunits, AtEH1 and AtEH2 function as scaffolds to drive biomolecular condensation of the complex. These condensates specifically nucleate on the plasma membrane through interactions with anionic phospholipids, and facilitate the dynamic recruitment and assembly of clathrin, early-, and late-stage endocytic accessory proteins. Importantly, clathrin forms ordered assemblies within the condensate environment. Biomolecular condensation therefore acts to promote dynamic protein assemblies throughout clathrin-mediated endocytosis. Furthermore, the disordered region sequence properties of AtEH1 regulate the material properties of the endocytic condensates in vivo. Alteration of the material properties influences endocytosis dynamics, and thereby impairs environmental adaption. In summary, our findings reveal how collective interactions shape endocytosis.
2023-12-07 | PXD045068 | Pride
Project description:Membrane tension regulated mechanotransduction drives fate transitions in embryonic stem cells
| PRJNA668927 | ENA
Project description:Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described so far through a hierarchical model in which elements of Hippo pathway are under the control of Focal Adhesions (FAs). Here we unveiled the molecular mechanism by which cell spreading and RhoA GTPase control FA formation through YAP to stabilize the anchorage of actin cytoskeleton to cell membrane. This mechanism required YAP co-transcriptional function and involved the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity led to the modification of cell mechanics, force development, adhesion strength, determined cell shaping, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify Hippo effector as the key determinant of cell mechanics in response to ECM cues.
2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress
Project description:The shape of a cell within tissues can represent the history of chemical and physical signals that it encounters, but can information from cell shape regulate cellular phenotype independently? Using optimal control theory to constrain reaction-diffusion schemes that are dependent on different surface-to-volume relationships, we find that information from cell shape can be resolved from mechanical signals. We used microfabricated 3-D biomimetic chips to validate predictions that shape-sensing occurs in a tension-independent manner through β3 integrin signaling pathway in human kidney podocytes and smooth muscle cells. Differential proteomics and functional ablation assays indicate that β3 integrin is critical in transduction of shape signals through ezrin-radixin-moesin (ERM) family. We used experimentally determined diffusion coefficients and experimentally validated simulations to show that shape sensing is an emergent cellular property enabled by multiple molecular characteristics of β3 integrin. We conclude that 3-D cell shape information, transduced through tension-independent mechanisms, can regulate phenotype.
2018-07-26 | PXD008150 | Pride
Project description:Understanding the topological configurations of chromatin can reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3-D interactions that undergo marked reorganization at the sub-Mb scale during differentiation. Distinct combinations of CTCF, Mediator, and cohesin show widespread enrichment in architecture at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant sub-domains. Conversely, Mediator/cohesin together with pioneer factors bridge short-range enhancer-promoter interactions within and between larger sub-domains. Knockdown of Smc1 or Med12 in ES cells results in disruption of spatial architecture and down-regulation of genes found in cohesin-mediated interactions. We conclude that cell type-specific chromatin organization occurs at the sub-Mb scale and that architectural proteins shape the genome in hierarchical length scales. Analysis of higher-order chromatin chromatin architecture in mouse ES cells and ES-derived NPCs. Analysis of CTCF and Smc1 occupied sites in ES-derived NPCs.
2013-05-24 | E-GEOD-36203 | biostudies-arrayexpress