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Injury primes mutation-bearing astrocytes for dedifferentiation in later life

Simpson Ragdale, Holly; Clements, Melanie; Tang, Wenhao; Deltcheva, Elitza; Andreassi, Catia; Lai, Alvina G; Chang, Wai Hoong; ... Parrinello, Simona; + view all (2023) Injury primes mutation-bearing astrocytes for dedifferentiation in later life. Current Biology 10.1016/j.cub.2023.02.013. (In press). Green open access

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Abstract

Despite their latent neurogenic potential, most normal parenchymal astrocytes fail to dedifferentiate to neural stem cells in response to injury. In contrast, aberrant lineage plasticity is a hallmark of gliomas, and this suggests that tumor suppressors may constrain astrocyte dedifferentiation. Here, we show that p53, one of the most commonly inactivated tumor suppressors in glioma, is a gatekeeper of astrocyte fate. In the context of stab-wound injury, p53 loss destabilized the identity of astrocytes, priming them to dedifferentiate in later life. This resulted from persistent and age-exacerbated neuroinflammation at the injury site and EGFR activation in periwound astrocytes. Mechanistically, dedifferentiation was driven by the synergistic upregulation of mTOR signaling downstream of p53 loss and EGFR, which reinstates stemness programs via increased translation of neurodevelopmental transcription factors. Thus, our findings suggest that first-hit mutations remove the barriers to injury-induced dedifferentiation by sensitizing somatic cells to inflammatory signals, with implications for tumorigenesis.

Type: Article
Title: Injury primes mutation-bearing astrocytes for dedifferentiation in later life
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cub.2023.02.013
Publisher version: https://doi.org/10.1016/j.cub.2023.02.013
Language: English
Additional information: © 2023 The Authors. Published by Elsevier Inc. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/).
Keywords: EGFR signaling, aging, astrocytes, brain injury, dedifferentiation, mTOR signaling, neural stem cells, neuroinflammation, p53
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10165848
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