A connexin43/YAP axis regulates astroglial-mesenchymal transition in hemoglobin induced astrocyte activation

Yong Yang; Jie Ren; Yuhao Sun; Yuan Xue; Zhijian Zhang; Aihua Gong; Baofeng Wang; Zhihong Zhong; Zhenwen Cui; Zhiyu Xi; Guo-Yuan Yang; Qingfang Sun; Liuguan Bian

doi:10.1038/s41418-018-0137-0

A connexin43/YAP axis regulates astroglial-mesenchymal transition in hemoglobin induced astrocyte activation

Cell Death Differ. 2018 Oct;25(10):1870-1884. doi: 10.1038/s41418-018-0137-0. Epub 2018 Jun 7.

Authors

Yong Yang^{1

2}, Jie Ren¹, Yuhao Sun¹, Yuan Xue³, Zhijian Zhang⁴, Aihua Gong⁴, Baofeng Wang¹, Zhihong Zhong¹, Zhenwen Cui⁵, Zhiyu Xi¹, Guo-Yuan Yang⁶, Qingfang Sun^{7

8}, Liuguan Bian⁹

Affiliations

¹ Department of Neurosurgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
² Department of Neurosurgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
³ Zhenjiang Center for Disease Control and Prevention, Zhenjiang, 212000, China.
⁴ Basic Medical Science Research Center, School of Medicine, Jiangsu University, Zhenjiang, 212000, China.
⁵ Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
⁶ Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
⁷ Department of Neurosurgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. sqf10756@rjh.com.cn.
⁸ Department of Neurosurgery, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University, Shanghai, 200025, China. sqf10756@rjh.com.cn.
⁹ Department of Neurosurgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. blg11118@rjh.com.cn.

Abstract

Reactive astrogliosis is a common response to insults to the central nervous system, but the mechanism remains unknown. In this study, we found the temporal and spatial differential expression of glial fibrillary acidic protein (GFAP) and Vimentin in the intracerebral hemorrhage (ICH) mouse brain, indicating that the de-differentiation and astroglial-mesenchymal transition (AMT) of astrocytes might be an early event in reactive astrogliosis. Further we verified the AMT finding in purified astrocyte cultures exposed to hemoglobin (Hb). Additionally, Connexin 43 (Cx43) downregulation and YAP nuclear translocation were observed in Hb-activated astrocytes. Knocking down Cx43 by siRNA triggered YAP nuclear translocation. Cx43 and YAP were physically associated as determined by immunofluorescence and co-immunoprecipitation. We propose that astrocytes undergo AMT during Hb-induced activation where Cx43 downregulation facilitates YAP nuclear translocation is a novel mechanism involved in this process. Cx43-YAP interaction may represent a potential therapeutic target for modulating astrocyte activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Astrocytes / cytology
Astrocytes / drug effects
Astrocytes / metabolism
Cell Cycle Proteins
Cell Nucleus / metabolism
Cell Proliferation
Cells, Cultured
Cerebral Hemorrhage / metabolism
Cerebral Hemorrhage / pathology
Connexin 43 / antagonists & inhibitors
Connexin 43 / genetics
Connexin 43 / metabolism*
Down-Regulation / drug effects
Epithelial-Mesenchymal Transition / drug effects*
Glial Fibrillary Acidic Protein / metabolism
Hemoglobins / pharmacology*
Interleukin-1beta / genetics
Interleukin-1beta / metabolism
Mice
Microscopy, Fluorescence
Phosphoproteins / chemistry
Phosphoproteins / metabolism*
Protein Binding
Protein Transport / drug effects
RNA Interference
RNA, Small Interfering / metabolism
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Connexin 43
Glial Fibrillary Acidic Protein
Hemoglobins
Interleukin-1beta
Phosphoproteins
RNA, Small Interfering
YAP-Signaling Proteins
Yap1 protein, mouse