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

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

  • Fluids Barriers CNS. 2024 Apr 8;21(1):32. doi: 10.1186/s12987-024-00533-9.
Shigeru Yamada 1 Tadahiro Hashita 2 Shota Yanagida 1 Hiroyuki Sato 2 Yukuto Yasuhiko 1 Kaori Okabe 3 Takamasa Noda 3 4 Motohiro Nishida 5 6 Tamihide Matsunaga 2 Yasunari Kanda 7
Affiliations

Affiliations

  • 1 Division of Pharmacology, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki-Ku, Kawasaki, 210-9501, Japan.
  • 2 Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
  • 3 Department of Psychiatry, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 4 Department of Brain Bioregulatory Science, The Jikei University Graduate School of Medicine, Tokyo, Japan.
  • 5 Department of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
  • 6 Division of Cardiocirculatory Signaling, National Institute for Physiological Sciences and Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki, Aichi, Japan.
  • 7 Division of Pharmacology, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki-Ku, Kawasaki, 210-9501, Japan. [email protected].
Abstract

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.

Keywords

BBB; Brain microvascular endothelial cells; CNS barrier; COVID-19; Inflammation; SARS-CoV-2; iPSC.

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