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ORIGINAL RESEARCH article

Front. Cell. Neurosci.
Sec. Non-Neuronal Cells
Volume 18 - 2024 | doi: 10.3389/fncel.2024.1487867
This article is part of the Research Topic The role of inflammatory processes in neurodegeneration: cellular, tissue and systemic mechanisms View all 3 articles

Tet2-mediated clonal hematopoiesis modestly improves neurological deficits and is associated with inflammation resolution in the subacute phase of experimental stroke

Provisionally accepted
Megan A Evans Megan A Evans 1Nicholas W Chavkin Nicholas W Chavkin 2Soichi Sano Soichi Sano 3Hanna Sun Hanna Sun 1Taneesha Sardana Taneesha Sardana 1Ramya Ravi Ramya Ravi 1Heather Doviak Heather Doviak 1YING WANG YING WANG 1Yoshimitsu Yura Yoshimitsu Yura 4Ariel H Polizio Ariel H Polizio 1Keita Horitani Keita Horitani 5Hayato Ogawa Hayato Ogawa 4Karen K Hirschi Karen K Hirschi 1Kenneth Walsh Kenneth Walsh 1*
  • 1 University of Virginia, Charlottesville, Virginia, United States
  • 2 University of Washington, Seattle, Washington, United States
  • 3 National Cerebral and Cardiovascular Center (Japan), Suita, Ôsaka, Japan
  • 4 Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan
  • 5 Kansai Medical University Osaka, Japan, Osaka, Japan

The final, formatted version of the article will be published soon.

    Recent work has revealed that clonal hematopoiesis (CH) is associated with a higher risk of numerous age-related diseases, including ischemic stroke, however little is known about whether it influences stroke outcome independent of its widespread effects on cardiovascular disease.Studies suggest that leukocytes carrying CH driver mutations have an enhanced inflammatory profile, which could conceivably exacerbate brain injury after a stroke. Using a competitive bone marrow transplant model of Tet2-mediated CH, we tested the hypothesis that CH would lead to a poorer outcome after ischemic stroke by augmenting brain inflammation. Stroke was induced in mice by middle cerebral artery occlusion and neurological outcome was assessed at acute (24 h) and subacute (14 d) timepoints. Brains were collected at both time points for histological, immunofluorescence and gene expression assays. Unexpectedly, Tet2-mediated CH had no effect on acute stroke outcome but led to a reduction in neurological deficits during the subacute phase. This improved neurological outcome was associated with lower levels of brain inflammation as evidenced by lower transcript levels of various inflammatory molecules alongside reduced astrogliosis. These findings suggest that Tet2-mediated clonal hematopoiesis may have beneficial effects on outcome after stroke, contrasting with the conventional understanding of clonal hematopoiesis whereby leukocytes with driver mutations promote disease by exacerbating inflammation.

    Keywords: TET2, ChIP, ischemic stroke, cerebral ischemia, Inflammation, Mouse

    Received: 28 Aug 2024; Accepted: 12 Nov 2024.

    Copyright: © 2024 Evans, Chavkin, Sano, Sun, Sardana, Ravi, Doviak, WANG, Yura, Polizio, Horitani, Ogawa, Hirschi and Walsh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Kenneth Walsh, University of Virginia, Charlottesville, 22904, Virginia, United States

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