The Experts below are selected from a list of 289623 Experts worldwide ranked by ideXlab platform
Andrea Zancla - One of the best experts on this subject based on the ideXlab platform.
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YAP–TEAD1 control of cytoskeleton dynamics and intraCellular tension guides human pluripotent stem Cell mesoderm specification
Cell Death & Differentiation, 2020Co-Authors: Stefania Pagliari, Vladimir Vinarsky, Fabiana Martino, Ana Rubina Perestrelo, Jorge Oliver De La Cruz, Guido Caluori, Jan Vrbsky, Pamela Mozetic, Antonio Pompeiano, Andrea ZanclaAbstract:The tight regulation of cytoskeleton dynamics is required for a number of Cellular processes, including migration, division and differentiation. YAP–TEAD respond to Cell–Cell interaction and to substrate mechanics and, among their downstream effects, prompt focal adhesion (FA) gene transcription, thus contributing to FA-cytoskeleton stability. This activity is key to the definition of Adult Cell mechanical properties and function. Its regulation and role in pluripotent stem Cells are poorly understood. Human PSCs display a sustained basal YAP-driven transcriptional activity despite they grow in very dense colonies, indicating these Cells are insensitive to contact inhibition. PSC inability to perceive Cell–Cell interactions can be restored by tampering with Tankyrase enzyme, thus favouring AMOT inhibition of YAP function. YAP–TEAD complex is promptly inactivated when germ layers are specified, and this event is needed to adjust PSC mechanical properties in response to physiological substrate stiffness. By providing evidence that YAP–TEAD1 complex targets key genes encoding for proteins involved in cytoskeleton dynamics, we suggest that substrate mechanics can direct PSC specification by influencing cytoskeleton arrangement and intraCellular tension. We propose an aberrant activation of YAP–TEAD1 axis alters PSC potency by inhibiting cytoskeleton dynamics, thus paralyzing the changes in shape requested for the acquisition of the given phenotype.
Elizabeth D Kirby - One of the best experts on this subject based on the ideXlab platform.
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poor concordance of floxed sequence recombination in single neural stem Cells implications for Cell autonomous studies
eNeuro, 2020Co-Authors: Tyler Joseph Dause, Elizabeth D KirbyAbstract:To manipulate target gene function in specific Adult Cell populations, tamoxifen (TAM)-dependent CreERT2 is widely used to drive inducible, site-specific recombination of loxP flanked sequences. In studies of Cell autonomous target gene function, it is common practice to combine these CreERT2-lox systems with a ubiquitously expressed stop-floxed fluorescent reporter gene to identify single Cells supposedly undergoing target gene recombination. Here, we studied the reliability of using Cre-induced recombination of one gene to predict recombination in another gene at the single-Cell level in Adult hippocampal neural stem and progenitor Cells (NSPCs). Using both probabilistic predictions in a generic experimental paradigm, as well as a mouse model with two separate stop-floxed reporters plus a Nestin promoter-driven CreERT2, we found that, in individual Cells, recombination of one gene was a poor predictor of recombination in another. This poor concordance in floxed sequence recombination across genes suggests that use of stop-floxed reporters to investigate Cell autonomous gene function may not be universally reliable and could lead to false conclusions.
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poor concordance of floxed sequence recombination in single neural stem Cells implications for Cell autonomous studies
bioRxiv, 2019Co-Authors: Tyler Joseph Dause, Elizabeth D KirbyAbstract:To manipulate target gene function in specific Adult Cell populations, tamoxifen-dependent CreERT2 is widely used to drive inducible, site-specific recombination of LoxP flanked sequences. In studies of Cell autonomous target gene function, it is common practice to combine these CreERT2-lox systems with a ubiquitously-expressed stop-floxed fluorescent reporter gene to identify single Cells supposedly undergoing target gene recombination. Here, we studied the reliability of using Cre-induced recombination of one gene to predict recombination in another gene at the single Cell level in Adult hippocampal neural stem and progenitor Cells. Using two separate stop-floxed reporters plus a Nestin promoter-driven CreERT2, we found that, in individual Cells, expression of one reporter was a poor predictor of expression of the other. These findings imply that use of stop-floxed reporters to investigate Cell autonomous gene function is likely to lead to false conclusions because recombination in separate genes shows poor concordance in individual Cells.
Pedro Luis Herrera - One of the best experts on this subject based on the ideXlab platform.
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mafa enables pdx1 to effectively convert pancreatic islet progenitors and committed islet α Cells into β Cells in vivo
Diabetes, 2017Co-Authors: Takaaki Matsuoka, Satoshi Kawashima, Takeshi Miyatsuka, Shugo Sasaki, Naoki Shimo, Naoto Katakami, Dan Kawamori, Satomi Takebe, Pedro Luis HerreraAbstract:Among the therapeutic avenues being explored for replacement of the functional islet β-Cell mass lost in type 1 diabetes (T1D), reprogramming of Adult Cell types into new β-Cells has been actively pursued. Notably, mouse islet α-Cells will transdifferentiate into β-Cells under conditions of near β-Cell loss, a condition similar to T1D. Moreover, human islet α-Cells also appear to poised for reprogramming into insulin-positive Cells. Here we have generated transgenic mice conditionally expressing the islet β-Cell–enriched Mafa and/or Pdx1 transcription factors to examine their potential to transdifferentiate embryonic pan–islet Cell Ngn3-positive progenitors and the later glucagon-positive α-Cell population into β-Cells. Mafa was found to both potentiate the ability of Pdx1 to induce β-Cell formation from Ngn3-positive endocrine precursors and enable Pdx1 to produce β-Cells from α-Cells. These results provide valuable insight into the fundamental mechanisms influencing islet Cell plasticity in vivo.
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conversion of Adult pancreatic α Cells to β Cells after extreme β Cell loss
Nature, 2010Co-Authors: Fabrizio Thorel, Virginie Nepote, Isabelle Avril, Renaud Desgraz, Simona Chera, Kenji Kohno, Pedro Luis HerreraAbstract:Pancreatic insulin-producing β-Cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, β-Cell loss). It is not known whether Adult mammals can differentiate (regenerate) new β-Cells after extreme, total β-Cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-β-Cell) source. Here we show β-Cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total β-Cell ablation. If given insulin, the mice survived and showed β-Cell mass augmentation with time. Lineage-tracing to label the glucagon-producing α-Cells before β-Cell ablation tracked large fractions of regenerated β-Cells as deriving from α-Cells, revealing a previously disregarded degree of pancreatic Cell plasticity. Such inter-endocrine spontaneous Adult Cell conversion could be harnessed towards methods of producing β-Cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration. The insulin-producing β-Cells of the pancreas are long lived and replicate little during a lifetime, but can duplicate upon injury or metabolic demand. Work in a transgenic mouse model in which β-Cells are nearly almost completely ablated shows that Adult α-Cells, normally responsible for producing the peptide hormone glucagon, can be spontaneously reprogrammed to become β-Cells. This unexpected display of pancreatic Cell plasticity suggests possible diabetes therapies involving either differentiation settings for in vitro Cell production or induced regeneration in vivo. And the production of new models for selective and total Cell killing could reveal previously unrecognized Cell plasticity in other organs. In the pancreas, insulin-producing β-Cells are long-lived and generally replicate seldom. They can do so, however, after increased metabolic demand or after injury. Here, a new transgenic model is developed in which β-Cells are nearly completely ablated in mice. If given insulin, these mice survive, and grow new β-Cells. Lineage-tracing shows that these new β-Cells come from α-Cells, revealing a previously disregarded degree of pancreatic Cell plasticity.
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conversion of Adult pancreatic alpha Cells to beta Cells after extreme beta Cell loss
Nature, 2010Co-Authors: Fabrizio Thorel, Virginie Nepote, Isabelle Avril, Renaud Desgraz, Simona Chera, Kenji Kohno, Pedro Luis HerreraAbstract:Pancreatic insulin-producing beta-Cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, beta-Cell loss). It is not known whether Adult mammals can differentiate (regenerate) new beta-Cells after extreme, total beta-Cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-beta-Cell) source. Here we show beta-Cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total beta-Cell ablation. If given insulin, the mice survived and showed beta-Cell mass augmentation with time. Lineage-tracing to label the glucagon-producing alpha-Cells before beta-Cell ablation tracked large fractions of regenerated beta-Cells as deriving from alpha-Cells, revealing a previously disregarded degree of pancreatic Cell plasticity. Such inter-endocrine spontaneous Adult Cell conversion could be harnessed towards methods of producing beta-Cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.
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conversion of Adult pancreatic α Cells to β Cells after extreme β Cell loss
Nature, 2010Co-Authors: Fabrizio Thorel, Virginie Nepote, Isabelle Avril, Renaud Desgraz, Simona Chera, Kenji Kohno, Pedro Luis HerreraAbstract:Pancreatic insulin-producing beta-Cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, beta-Cell loss). It is not known whether Adult mammals can differentiate (regenerate) new beta-Cells after extreme, total beta-Cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-beta-Cell) source. Here we show beta-Cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total beta-Cell ablation. If given insulin, the mice survived and showed beta-Cell mass augmentation with time. Lineage-tracing to label the glucagon-producing alpha-Cells before beta-Cell ablation tracked large fractions of regenerated beta-Cells as deriving from alpha-Cells, revealing a previously disregarded degree of pancreatic Cell plasticity. Such inter-endocrine spontaneous Adult Cell conversion could be harnessed towards methods of producing beta-Cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.
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conversion of Adult pancreatic a Cells to b Cells after extreme b Cell loss
2010Co-Authors: Fabrizio Thorel, Isabelle Avril, Renaud Desgraz, Simona Chera, Kenji Kohno, Pedro Luis HerreraAbstract:Pancreaticinsulin-producingb-Cellshavealonglifespan,suchthatinhealthyconditionstheyreplicatelittleduringalifetime. Nevertheless,theyshowincreasedself-duplicationafterincreasedmetabolicdemandorafterinjury(thatis,b-Cellloss).Itis not known whether Adult mammals can differentiate (regenerate) new b-Cells after extreme, total b-Cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-b-Cell) source. Here we show b-Cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-totalb-Cell ablation. If given insulin, the mice survived and showed b-Cell mass augmentation with time. Lineage-tracing to label the glucagon-producing a-Cells before b-Cell ablation tracked large fractions of regenerated b-Cells as deriving from a-Cells, revealing a previously disregarded degree of pancreatic Cell plasticity. Such inter-endocrine spontaneous Adult Cell conversion could be harnessed towards methods of producing b-Cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.
Roland Stein - One of the best experts on this subject based on the ideXlab platform.
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dynamic recruitment of functionally distinct swi snf chromatin remodeling complexes modulates pdx1 activity in islet β Cells
Cell Reports, 2015Co-Authors: Brian Mckenna, Min Guo, Albert B Reynolds, Manami Hara, Roland SteinAbstract:Pdx1 is a transcription factor of fundamental importance to pancreas formation and Adult islet β Cell function. However, little is known about the positive- and negative-acting coregulators recruited to mediate transcriptional control. Here, we isolated numerous Pdx1-interacting factors possessing a wide range of Cellular functions linked with this protein, including, but not limited to, coregulators associated with transcriptional activation and repression, DNA damage response, and DNA replication. Because chromatin remodeling activities are essential to developmental lineage decisions and Adult Cell function, our analysis focused on investigating the influence of the Swi/Snf chromatin remodeler on Pdx1 action. The two mutually exclusive and indispensable Swi/Snf core ATPase subunits, Brg1 and Brm, distinctly affected target gene expression in β Cells. Furthermore, physiological and pathophysiological conditions dynamically regulated Pdx1 binding to these Swi/Snf complexes in vivo. We discuss how context-dependent recruitment of coregulatory complexes by Pdx1 could impact pancreas Cell development and Adult islet β Cell activity.
Stefania Pagliari - One of the best experts on this subject based on the ideXlab platform.
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YAP–TEAD1 control of cytoskeleton dynamics and intraCellular tension guides human pluripotent stem Cell mesoderm specification
Cell Death & Differentiation, 2020Co-Authors: Stefania Pagliari, Vladimir Vinarsky, Fabiana Martino, Ana Rubina Perestrelo, Jorge Oliver De La Cruz, Guido Caluori, Jan Vrbsky, Pamela Mozetic, Antonio Pompeiano, Andrea ZanclaAbstract:The tight regulation of cytoskeleton dynamics is required for a number of Cellular processes, including migration, division and differentiation. YAP–TEAD respond to Cell–Cell interaction and to substrate mechanics and, among their downstream effects, prompt focal adhesion (FA) gene transcription, thus contributing to FA-cytoskeleton stability. This activity is key to the definition of Adult Cell mechanical properties and function. Its regulation and role in pluripotent stem Cells are poorly understood. Human PSCs display a sustained basal YAP-driven transcriptional activity despite they grow in very dense colonies, indicating these Cells are insensitive to contact inhibition. PSC inability to perceive Cell–Cell interactions can be restored by tampering with Tankyrase enzyme, thus favouring AMOT inhibition of YAP function. YAP–TEAD complex is promptly inactivated when germ layers are specified, and this event is needed to adjust PSC mechanical properties in response to physiological substrate stiffness. By providing evidence that YAP–TEAD1 complex targets key genes encoding for proteins involved in cytoskeleton dynamics, we suggest that substrate mechanics can direct PSC specification by influencing cytoskeleton arrangement and intraCellular tension. We propose an aberrant activation of YAP–TEAD1 axis alters PSC potency by inhibiting cytoskeleton dynamics, thus paralyzing the changes in shape requested for the acquisition of the given phenotype.