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Redox Heterogeneity in Mouse Embryonic Stem Cells Individualizes Cell Fate Decisions

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE244780 | GEO | 2024/07/07

REPOSITORIES: GEO

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Redox Heterogeneity in Mouse Embryonic Stem Cells Individualizes Cell Fate Decisions II

Project description:How cellular diversity is created is a key question in biology. Embryonic stem cells (ESCs) are pluripotent cells that can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions remain largely unknown. Moreover, although genetically identical, individual ESCs are strikingly heterogeneous regarding their differentiation capacity but the molecular basis for this phenotypic heterogeneity is unclear. We now demonstrate that pluripotent mouse ESCs (mESCs) display large natural variations in mitochondrial reactive oxygen species (ROS) levels that individualize their nuclear redox state and redox-sensitive H3K4me3 landscape. By using intracellular redox probes, we sorted pluripotent and differentiating mESCs based on their nuclear redox environments into subpopulations and analysed their differentiation capacity. We show that more reduced mESCs are biased towards the mesendodermal fate and form the primitive streak upon differentiation. This mesendodermal specification is due to increased Wnt signaling pathway activity, mediated via a ROS-specific regulatory mechanism of p53-dependent expression of the Wnt ligand Wnt3, and increased H3K4me3 levels. We demonstrate that formation of a primitive streak-like structure by differentiating mESCs is initiated by increased mitochondrial ROS and p53 stabilization, followed by antioxidant Nrf2 response pathway activation that leads to a reduced nuclear redox environment, allowing for the accumulation of ROS-sensitive H3K4me3 marks and activation of Wnt3 and other mesendoderm-related gene expression. In summary, our study shows that natural variations in endogenous ROS levels individualize the H3K4me3 landscape of mESCs, and through gene expression changes govern their cell fate decision at the onset of gastrulation.

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Redox Heterogeneity in Mouse Embryonic Stem Cells Individualizes Cell Fate Decisions I

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Redox Heterogeneity in Mouse Embryonic Stem Cells Individualizes Cell Fate Decisions

Project description:Redox Heterogeneity in Mouse Embryonic Stem Cells Individualizes Cell Fate Decisions

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Redox Heterogeneity in Mouse Embryonic Stem Cells Individualizes Cell Fate Decisions I

Project description:Redox Heterogeneity in Mouse Embryonic Stem Cells Individualizes Cell Fate Decisions I

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Project description:Research on human embryonic stem cells (hESCs) has attracted much attention given their great potential for tissue regenerative therapy and fundamental developmental biology studies. Yet, there is still limited understanding of how mechanical signals in the local cellular microenvironment of hESCs regulate their fate decisions. Here, we applied a microfabricated micromechanical platform to investigate the mechanoresponsive behaviors of hESCs. We demonstrated that hESCs are mechanosensitive, and they could increase their cytoskeleton contractility with matrix rigidity. Furthermore, rigid substrates supported maintenance of pluripotency of hESCs. Matrix mechanics-mediated cytoskeleton contractility might be functionally correlated with E-cadherin expressions in cell-cell contacts and thus involved in fate decisions of hESCs. Our results highlighted the important functional link between matrix rigidity, cellular mechanics, and pluripotency of hESCs and provided a novel approach to characterize and understand mechanotransduction and its involvement in hESC function.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Project description:This SuperSeries is composed of the SubSeries listed below.

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