SARS-CoV-2 spike protein induces endothelial dysfunction in 3D engineered vascular networks

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Virology

Background:

• Long-term impacts of COVID-19 necessitate better in vitro models to study disease mechanisms.
• Endothelial dysfunction is a key feature of severe COVID-19, contributing to organ damage.
• Existing models often lack the complexity to fully replicate in vivo conditions.

Purpose of the Study:

• To develop and validate a 3D in vitro model of endothelial dysfunction using human induced pluripotent stem cell-derived endothelial progenitors.
• To investigate the specific effects of SARS-CoV-2 spike protein on vascular network formation and function.
• To explore potential therapeutic interventions for COVID-19-induced vascular complications.

Main Methods:

• Human induced pluripotent stem cell-derived endothelial progenitors were encapsulated in collagen hydrogels.
• The 3D cell-laden hydrogels were treated with SARS-CoV-2 spike protein (SP).
• Vessel formation, network connectivity, and inflammatory cytokine release were quantified; dexamethasone was used as a therapeutic agent.

Main Results:

• The model successfully formed capillary-like vasculature within one week.
• Treatment with SARS-CoV-2 SP significantly reduced vessel formation and network connectivity, a phenomenon specific to SARS-CoV-2.
• SARS-CoV-2 SP treatment increased inflammatory cytokine release, mimicking the COVID-19 cytokine storm, and dexamethasone prevented this dysfunction.

Conclusions:

• The 3D in vitro model accurately reproduces COVID-19-induced endothelial dysfunction, even without immune cells.
• This model is crucial for understanding SARS-CoV-2 interactions with the endothelium and the pathogenesis of long COVID.
• The findings support the development of targeted therapeutics for COVID-19 vascular complications.