Blood-perfused Vessels-on-Chips stimulated with patient plasma recapitulate endothelial activation and microthrombosis in COVID-19

Huub J. Weener*, Thijs F. van Haaps, Ruben W.J. van Helden, Hugo J. Albers, Rozemarijn Haverkate, Heleen H.T. Middelkamp, Milan L. Ridderikhof, Thijs E. van Mens, Albert van den Berg, Christine L. Mummery, Valeria V. Orlova, Saskia Middeldorp, Nick van Es, Andries D. van der Meer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

A subset of coronavirus disease 2019 (COVID-19) patients develops severe symptoms, characterized by acute lung injury, endothelial dysfunction and microthrombosis. Viral infection and immune cell activation contribute to this phenotype. It is known that systemic inflammation, evidenced by circulating inflammatory factors in patient plasma, is also likely to be involved in the pathophysiology of severe COVID-19. Here, we evaluate whether systemic inflammatory factors can induce endothelial dysfunction and subsequent thromboinflammation. We use a microfluidic Vessel-on-Chip model lined by human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs), stimulate it with plasma from hospitalized COVID-19 patients and perfuse it with human whole blood. COVID-19 plasma exhibited elevated levels of inflammatory cytokines compared to plasma from healthy controls. Incubation of hiPSC-ECs with COVID-19 plasma showed an activated endothelial phenotype, characterized by upregulation of inflammatory markers and transcriptomic patterns of host defense against viral infection. Treatment with COVID-19 plasma induced increased platelet aggregation in the Vessel-on-Chip, which was associated partially with formation of neutrophil extracellular traps (NETosis). Our study demonstrates that factors in the plasma play a causative role in thromboinflammation in the context of COVID-19. The presented Vessel-on-Chip can enable future studies on diagnosis, prevention and treatment of severe COVID-19.

Original languageEnglish
Pages (from-to)1787-1800
Number of pages14
JournalLab on a chip
Volume25
Issue number7
Early online date2025
DOIs
Publication statusPublished - 7 Apr 2025

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