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Endothelial cells regulate astrocyte to neural progenitor cell trans-differentiation in a mouse model of stroke

Author

Listed:
  • Wenlu Li

    (Harvard Medical School)

  • Emiri T. Mandeville

    (Harvard Medical School)

  • Violeta Durán-Laforet

    (Harvard Medical School
    Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre)

  • Norito Fukuda

    (Harvard Medical School)

  • Zhanyang Yu

    (Harvard Medical School)

  • Yi Zheng

    (Harvard Medical School)

  • Aaron Held

    (Harvard Medical School)

  • Ji-Hyun Park

    (Harvard Medical School)

  • Takafumi Nakano

    (Harvard Medical School)

  • Masayoshi Tanaka

    (Harvard Medical School)

  • Jingfei Shi

    (Harvard Medical School
    Capital Medical University)

  • Elga Esposito

    (Harvard Medical School)

  • Wanting Niu

    (VA Boston Healthcare System
    Harvard Medical School)

  • Changhong Xing

    (Harvard Medical School)

  • Kazuhide Hayakawa

    (Harvard Medical School)

  • Ignacio Lizasoain

    (Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre)

  • Klaus Leyen

    (Harvard Medical School)

  • Xunming Ji

    (Capital Medical University)

  • Brian J. Wainger

    (Harvard Medical School)

  • Maria A. Moro

    (Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC))

  • Eng H. Lo

    (Harvard Medical School)

Abstract

The concept of the neurovascular unit emphasizes the importance of cell-cell signaling between neural, glial, and vascular compartments. In neurogenesis, for example, brain endothelial cells play a key role by supplying trophic support to neural progenitors. Here, we describe a surprising phenomenon where brain endothelial cells may release trans-differentiation signals that convert astrocytes into neural progenitor cells in male mice after stroke. After oxygen-glucose deprivation, brain endothelial cells release microvesicles containing pro-neural factor Ascl1 that enter into astrocytes to induce their trans-differentiation into neural progenitors. In mouse models of focal cerebral ischemia, Ascl1 is upregulated in endothelium prior to astrocytic conversion into neural progenitor cells. Injecting brain endothelial-derived microvesicles amplifies the process of astrocyte trans-differentiation. Endothelial-specific overexpression of Ascl1 increases the local conversion of astrocytes into neural progenitors and improves behavioral recovery. Our findings describe an unexpected vascular-regulated mechanism of neuroplasticity that may open up therapeutic opportunities for improving outcomes after stroke.

Suggested Citation

  • Wenlu Li & Emiri T. Mandeville & Violeta Durán-Laforet & Norito Fukuda & Zhanyang Yu & Yi Zheng & Aaron Held & Ji-Hyun Park & Takafumi Nakano & Masayoshi Tanaka & Jingfei Shi & Elga Esposito & Wanting, 2022. "Endothelial cells regulate astrocyte to neural progenitor cell trans-differentiation in a mouse model of stroke," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35498-6
    DOI: 10.1038/s41467-022-35498-6
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    References listed on IDEAS

    as
    1. Mark A. Anderson & Joshua E. Burda & Yilong Ren & Yan Ao & Timothy M. O’Shea & Riki Kawaguchi & Giovanni Coppola & Baljit S. Khakh & Timothy J. Deming & Michael V. Sofroniew, 2016. "Astrocyte scar formation aids central nervous system axon regeneration," Nature, Nature, vol. 532(7598), pages 195-200, April.
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    3. Andrew Grande & Kyoko Sumiyoshi & Alejandro López-Juárez & Jennifer Howard & Bhuvaneswari Sakthivel & Bruce Aronow & Kenneth Campbell & Masato Nakafuku, 2013. "Environmental impact on direct neuronal reprogramming in vivo in the adult brain," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
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