Journal Article

SARS-CoV-2 causes dysfunction in human iPSC-derived brain microvascular endothelial cells potentially by modulating the Wnt signaling pathway

Nishida, Motohiro, Kanda, Yasunari, Yasuhiko, Yukuto, Okabe, Kaori, Sato, Hiroyuki, Hashita, Tadahiro, Yanagida, Shota, Yamada, Shigeru, Noda, Takamasa, Matsunaga, Tamihide

2024

Overview

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which is associated with various neurological symptoms, including nausea, dizziness, headache, encephalitis, and epileptic seizures. SARS-CoV-2 is considered to affect the central nervous system (CNS) by interacting with the blood–brain barrier (BBB), which is defined by tight junctions that seal paracellular gaps between brain microvascular endothelial cells (BMECs). Although SARS-CoV-2 infection of BMECs has been reported, the detailed mechanism has not been fully elucidated. Methods Using the original strain of SARS-CoV-2, the infection in BMECs was confirmed by a detection of intracellular RNA copy number and localization of viral particles. BMEC functions were evaluated by measuring transendothelial electrical resistance (TEER), which evaluates the integrity of tight junction dynamics, and expression levels of proinflammatory genes. BMEC signaling pathway was examined by comprehensive RNA-seq analysis. Results We observed that iPSC derived brain microvascular endothelial like cells (iPSC-BMELCs) were infected with SARS-CoV-2. SARS-CoV-2 infection resulted in decreased TEER. In addition, SARS-CoV-2 infection decreased expression levels of tight junction markers CLDN3 and CLDN11 . SARS-CoV-2 infection also increased expression levels of proinflammatory genes, which are known to be elevated in patients with COVID-19. Furthermore, RNA-seq analysis revealed that SARS-CoV-2 dysregulated the canonical Wnt signaling pathway in iPSC-BMELCs. Modulation of the Wnt signaling by CHIR99021 partially inhibited the infection and the subsequent inflammatory responses. Conclusion These findings suggest that SARS-CoV-2 infection causes BBB dysfunction via Wnt signaling. Thus, iPSC-BMELCs are a useful in vitro model for elucidating COVID-19 neuropathology and drug development.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / B cells / BBB / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Brain microvascular endothelial cells / Brain research / Cell culture / Central nervous system / CNS barrier / Copy number / Coronaviruses / COVID-19 / Drug development / Electric properties / Electrical resistivity / Encephalitis / Endothelial cells / Endothelium / Epilepsy / Genes / Health aspects / Hematology / Infections / Inflammation / Invoices / iPSC / Localization / Medical research / Medicine, Experimental / Methylene blue / Microvasculature / Nausea / Neurobiology / Neurosciences / Ribonucleic acid / RNA / SARS-CoV-2 / Scientific equipment and supplies industry / Seizures / Seizures (Medicine) / Sequence analysis / Severe acute respiratory syndrome coronavirus 2 / Signal transduction / Tight junctions / Wnt protein