Neonatal hypoxic-ischemic encephalopathy (HIE) with the pathological characteristic of white matter injury often leads to lifelong cognitive and neurobehavioral dysfunction, but relevant therapies to promote remyelination are still unavailable. We found that histamine H2 receptor (H2R) negatively regulated the oligodendrocyte differentiation rate without affecting the oligodendrocytes at the oligodendrocyte precursor cell stage or mature stage following oxygen-glucose deprivation in vitro. Notably, selective deletion of the H2R gene (Hrh2) in differentiating oligodendrocytes (Hrh2fl/fl;CNPase-Cre) improved their differentiation, remyelination, and functional recovery following neonatal hypoxia-ischemia in mice. The regulation of oligodendrocyte differentiation by H2R is mediated by binding with Axin2, which leads to up-regulation of the Wnt/β-catenin signaling pathway. Furthermore, H2R antagonists also promoted oligodendrocyte differentiation and remyelination and the recovery of cognition and motor functions following neonatal hypoxia-ischemia. Thus, histamine H2R in oligodendrocytes could serve as a novel and effective therapeutic target for the retard of oligodendrocyte differentiation and remyelination following neonatal hypoxia-ischemia. The H2R antagonists may have potential therapeutic value for neonatal HIE.
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4 January 2021
Article|
September 29 2020
Histamine H2 receptor negatively regulates oligodendrocyte differentiation in neonatal hypoxic-ischemic white matter injury
Lei Jiang
,
Lei Jiang
*
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Validation, Visualization, Writing - original draft
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Li Cheng
,
Li Cheng
*
Data curation, Formal analysis, Validation, Visualization, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Han Chen
,
Han Chen
Investigation
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Haibin Dai
,
Haibin Dai
Conceptualization, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Dadao An
,
Dadao An
Methodology
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Qianyi Ma
,
Qianyi Ma
Data curation
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Yanrong Zheng
,
Yanrong Zheng
Formal analysis, Validation, Visualization
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Xiangnan Zhang
,
Xiangnan Zhang
Conceptualization, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Weiwei Hu
,
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Correspondence to Weiwei Hu: huww@zju.edu.cn
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Zhong Chen
Zhong Chen
Conceptualization, Funding acquisition, Supervision, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
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Lei Jiang
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Validation, Visualization, Writing - original draft
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Li Cheng
Data curation, Formal analysis, Validation, Visualization, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Han Chen
Investigation
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Haibin Dai
Conceptualization, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Dadao An
Methodology
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Qianyi Ma
Data curation
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Yanrong Zheng
Formal analysis, Validation, Visualization
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Xiangnan Zhang
Conceptualization, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Weiwei Hu
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
Zhong Chen
Conceptualization, Funding acquisition, Supervision, Writing - review & editing
Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China
*
L. Jiang and L. Cheng contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Correspondence to Weiwei Hu: huww@zju.edu.cn
Received:
July 24 2019
Revision Received:
February 19 2020
Accepted:
April 27 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Natural Science Foundation of China
(81722045, 81673405, 81872844, 81973302)
© 2020 Jiang et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (1): e20191365.
Article history
Received:
July 24 2019
Revision Received:
February 19 2020
Accepted:
April 27 2020
Citation
Lei Jiang, Li Cheng, Han Chen, Haibin Dai, Dadao An, Qianyi Ma, Yanrong Zheng, Xiangnan Zhang, Weiwei Hu, Zhong Chen; Histamine H2 receptor negatively regulates oligodendrocyte differentiation in neonatal hypoxic-ischemic white matter injury. J Exp Med 4 January 2021; 218 (1): e20191365. doi: https://doi.org/10.1084/jem.20191365
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