Hyperosmotic stress induces 2-cell-like cells through ROS and ATR signaling
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ABSTRACT:
PROVIDER: PRJNA966121 | ENA |
REPOSITORIES: ENA
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Project description:Mouse embryonic stem cells (ESCs) display pluripotency features characteristic of the inner cell mass of the blastocyst. ESC cultures are highly heterogeneous and include a rare population of cells, which recapitulate characteristics of the 2-cell embryo, referred to as 2-cell-like cells (2CLCs). Whether and how ESC and 2CLC respond to environmental cues has not been fully elucidated. Here, we investigate the impact of mechanical stress on the reprogramming of ESC to 2CLC. We show that hyperosmotic stress induces 2CLC and that this induction can occur even after a recovery time from hyperosmotic stress, suggesting a memory response. Hyperosmotic stress in ESCs leads to accumulation of reactive-oxygen species (ROS) as well as ATR checkpoint activation. Importantly, preventing either elevated ROS levels or ATR activation impairs hyperosmotic-mediated 2CLC induction. We further show that ROS generation and the ATR checkpoint act within the same molecular pathway in response to hyperosmotic stress to induce 2CLCs. Altogether, these results shed light on the response of ESC to mechanical stress and on our understanding of 2CLC reprogramming.
2023-08-15 | GSE231475 | GEO
Project description:Mouse embryonic stem cells (ESCs) display pluripotency features characteristic of the inner cell mass of the blastocyst. ESC cultures are highly heterogeneous and include a rare population of cells, which recapitulate characteristics of the 2-cell embryo, referred to as 2-cell-like cells (2CLCs). Whether and how ESC and 2CLC respond to environmental cues has not been fully elucidated. Here, we investigate the impact of mechanical stress on the reprogramming of ESC to 2CLC. We show that hyperosmotic stress induces 2CLC and that this induction can occur even after a recovery time from hyperosmotic stress, suggesting a memory response. Hyperosmotic stress in ESCs leads to accumulation of reactive-oxygen species (ROS) as well as ATR checkpoint activation. Importantly, preventing either elevated ROS levels or ATR activation impairs hyperosmotic-mediated 2CLC induction. We further show that ROS generation and the ATR checkpoint act within the same molecular pathway in response to hyperosmotic stress to induce 2CLCs. Altogether, these results shed light on the response of ESC to mechanical stress and on our understanding of 2CLC reprogramming.
| S-SCDT-10_15252-EMBR_202256194 | biostudies-other
Project description:Mouse embryonic stem cells (ESCs) display pluripotency features characteristic of the inner cell mass of the blastocyst. Mouse embryonic stem cell cultures are highly heterogeneous and include a rare population of cells, which recapitulate characteristics of the 2-cell embryo, referred to as 2-cell-like cells (2CLCs). Whether and how ESC and 2CLC respond to environmental cues has not been fully elucidated. Here, we investigate the impact of mechanical stress on the reprogramming of ESC to 2CLC. We show that hyperosmotic stress induces 2CLC and that this induction can occur even after a recovery time from hyperosmotic stress, suggesting a memory response. Hyperosmotic stress in ESCs leads to accumulation of reactive-oxygen species (ROS) and ATR checkpoint activation. Importantly, preventing either elevated ROS levels or ATR activation impairs hyperosmotic-mediated 2CLC induction. We further show that ROS generation and the ATR checkpoint act within the same molecular pathway in response to hyperosmotic stress to induce 2CLCs. Altogether, these results shed light on the response of ESC to mechanical stress and on our understanding of 2CLC reprogramming.
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2013-08-31 | GSE47170 | GEO
Project description:Mitochondria are the central metabolic hub of the cell and their function is vital for cellular activities. Mitochondrial autophagy, or mitophagy, is a quality control mechanism to surveille the fitness and functionality of mitochondria and is therefore essential for life. Both mitochondrial dysfunction and malfunctional DNA damage response (DDR) are a major etiology for tissue impairment and aging. ATR has been shown mainly as a nuclear factor to conduct DNA damage response under DNA replication stress. Paradoxically, the human Seckel syndrome caused by ATR mutations is characterized by premature aging and neuropathies, suggesting a role of ATR in non-replicating tissues. Here we report a previously unknown yet direct role of ATR at mitochondria. We find that HSP90 chaperones ATR and PINK1 to mitochondria, where ATR interacts with and thereby stabilizes PINK1 docking at the mitochondrial translocase TOM/TIM complex as well as with the electron transport chain (ETC). ATR mutant cells are refractory to mitophagy initiation, which can be reverted by an ectopic expression of full length, but not ATR-interaction mutant, PINK1. ATR deletion alters mitochondrial dynamics and OXPHOS functions producing aberrantly high reactive oxygen species (ROS) that attack cytosolic macromolecules prior to damaging nuclear DNA. Intriguingly, pharmacological intervention of mitochondrial metabolism to prevent ROS overproduction can mute ATR-mediated nuclear DDR. This study demonstrates that ATR is an integrated component of the mitochondrial membrane to ensure mitochondrial fitness as a primary physiological function, which, together with its essential DDR function, safeguards the cell fate under physiological and genotoxic conditions.
2025-02-26 | GSE244464 | GEO
Project description:Oral streptococci metabolize carbohydrate to produce organic acids, not only decrease the environmental pH, but also increase osmolality of dental plaque fluid due to tooth demineralization and consequent calcium and phosphate accumulation. Thus, to persevere in the dental plaque, acidogenic bacteria should evolve sophisticated molecular machineries to counter the detrimental effect of elevated osmolality. This study was aimed to obtain a global view on strategies taken by streptococcus mutans to deal with physiologically relevant elevated osmolality, and preserves within a cariogenic dental plaque. We investigated phenotypic change of S. mutans biofilm upon sub-lethal level of hyperosmotic challenge. We found that hyperosmotic condition was able to initiate S. mutans biofilm dispersal by reducing both microbial content and extracellular polysaccharides matrix. We then used DNA microarray with qPCR validation to systemically investigate the underlying molecular machinery of this bacteria in response to hyperosmotic stimuli. Among those identified 50 differentially regulated genes, down-regulation of gtfB and comC were believed to be responsible for the observed biofilm dispersal. Further analysis of microarray data showed significant up-regulation of genes and pathways involved in carbohydrates metabolism. Specific genes involved in heat shock response and acid tolerance were also upregulated, indicating potential cross-talk between hyperosmotic and other environmental stress. Based on the data obtained in this study, we believe that although hyperosmotic condition may induce significant stress response on S. mutans, this cariogenic bacterium has evolved sophisticated molecular machineries to counter those elicited detrimental effects. In the meantime, it will take full advantage of these environmental stimuli to better fit the fluctuating environments within oral cavity, and thus emerge as numeric-predominant bacteria under cariogenic conditions. A six-chip study using total RNA recovered from mid-logarithmic phase of S. mutans UA159 from three separate cultures of strains submitted for 15 minutes to hyperosmotic stimuli (0.4M NaCl) and three separate cultures of strains kept under no stress condition.
2013-08-31 | E-GEOD-47170 | biostudies-arrayexpress
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