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

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 Niu, Changhong Xing, Kazuhide Hayakawa, Ignacio Lizasoain, Klaus Leyen, Xunming Ji, Brian J. Wainger, Maria A. Moro and Eng H. Lo ()
Additional contact information
Wenlu Li: Harvard Medical School
Emiri T. Mandeville: Harvard Medical School
Violeta Durán-Laforet: Harvard Medical School
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
Elga Esposito: Harvard Medical School
Wanting Niu: VA Boston Healthcare System
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

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35498-6

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