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March 08, 2023

Using organ-on-a-chip technology to elucidate the liver pathophysiology of COVID-19 patients

Junior Associate Professor Kazuo Takayama and his research group developed liver-on-a-chips (LoCs) with bile duct or blood vessel-like structures to investigate the liver pathology of patients with COVID-19 and demonstrated their utility for evaluating drug efficacy.

SARS-CoV-2 infects and causes damage to multiple organs in COVID-19 patients. In particular, liver damage has been associated with COVID-19 severity. However, the appreciation for the liver pathophysiology of these patients remains largely incomplete.

To better understand the liver pathophysiology of COVID-19 patients, the group developed liver models that mimic the liver around blood vessels or bile ducts using organ-on-a-chip technology. Human hepatocytes and cholangiocytes (bile duct epithelial cells) were cultured in the top and bottom channels of microfluidic devices, respectively, to create the liver-on-a-chip with intrahepatic bile duct (ibd-LoC). Similarly, human hepatocytes and vascular endothelial cells were cultured in adjacent channels of microfluidic devices to produce the liver-on-a-chip with a blood vessel (bv-LoC).

The researchers infected these LoCs with SARS-CoV-2 to model the liver pathophysiology of COVID-19 patients and detected the virus in both ibd-LoCs and bv-LoCs two days following infection. Interestingly, despite observing viral clearance after two weeks, increased hepatotoxicity and lipid droplet accumulation continued in the infected bv-LoCs, but not in the infected ibd-LoCs. These findings suggest that the vascularized parts of the liver are more vulnerable to damage by SARS-CoV-2 infection, and such damage is responsible for the liver dysfunctions experienced by COVID-19 patients.

Furthermore, the team screened for therapeutic drugs that can treat these liver abnormalities and found the combined treatment of remdesivir and baricitinib to significantly reduce the hepatotoxicity and lipid droplet accumulation observed in the infected bv-LoCs, suggesting that these two drugs could be effective to treat liver injuries caused by SARS-CoV-2 infection.

Organs-on-a-chip technology, such as the ones described in this study, will help to broaden the understanding of organ dysfunctions in COVID-19 patients and accelerate the development of therapeutic agents to treat this catastrophic disease.

The results of this research were published online in PNAS Nexus on March 7, 2023.

Paper Details
  • Journal: PNAS Nexus
  • Title: Elucidation of the liver pathophysiology of COVID-19 patients using liver-on-a chips
  • Authors: Sayaka Deguchi1,2, Kaori Kosugi1, Rina Hashimoto1, Ayaka Sakamoto1, Masaki Yamamoto3, Rafal P. Krol4, Peter Gee5, Ryosuke Negoro6, Takeshi Noda7,8, Takuya Yamamoto1,9,10, Yu-suke Torisawa11, Miki Nagao3, Kazuo Takayama1,12,*
    * Corresponding Author
  • Author Affiliations:
    1. Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    2. Department of Medical Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    3. Department of Clinical Laboratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    4. CiRA Foundation, Research and Development Center, Kyoto, Japan
    5. MaxCyte, Inc., Gaithersburg, United States of America
    6. Laboratory of Molecular Pharmacokinetics, College of Pharmaceutical Sciences, Ritsumeikan University, Noji-Higashi, Kusatsu, Japan
    7. Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
    8. CREST, Japan Science and Technology Agency (JST), Kawaguchi, Japan
    9. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
    10. Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan
    11. Department of Micro Engineering, Kyoto University, Kyoto, Japan
    12. AMED-CREST, Japan Agency for Medical Research and Development (AMED), Tokyo, Japan
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