SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection
Abstract Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the incr...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54917-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850048456240922624 |
|---|---|
| author | Alexsia Richards Andrew S. Khalil Max Friesen Troy W. Whitfield Xinlei Gao Tenzin Lungjangwa Roger D. Kamm Zhengpeng Wan Lee Gehrke David Mooney Rudolf Jaenisch |
| author_facet | Alexsia Richards Andrew S. Khalil Max Friesen Troy W. Whitfield Xinlei Gao Tenzin Lungjangwa Roger D. Kamm Zhengpeng Wan Lee Gehrke David Mooney Rudolf Jaenisch |
| author_sort | Alexsia Richards |
| collection | DOAJ |
| description | Abstract Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here, we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly SMCs, are a susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterize the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, PCs, and ECs. We observe that infected SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we show human ECs exposed to the secretome of infected SMCs produce hemostatic factors that contribute to vascular dysfunction despite not being susceptible to direct infection. The findings here recapitulate observations from patient sera in human COVID-19 patients and provide mechanistic insight into the unique vascular implications of SARS-CoV-2 infection at a cellular level. |
| format | Article |
| id | doaj-art-bdf14bbc35fa45d78d9c8ca17866aa9a |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bdf14bbc35fa45d78d9c8ca17866aa9a2025-08-20T02:53:57ZengNature PortfolioNature Communications2041-17232024-12-0115111710.1038/s41467-024-54917-4SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infectionAlexsia Richards0Andrew S. Khalil1Max Friesen2Troy W. Whitfield3Xinlei Gao4Tenzin Lungjangwa5Roger D. Kamm6Zhengpeng Wan7Lee Gehrke8David Mooney9Rudolf Jaenisch10Whitehead Institute for Biomedical ResearchWhitehead Institute for Biomedical ResearchWhitehead Institute for Biomedical ResearchWhitehead Institute for Biomedical ResearchWhitehead Institute for Biomedical ResearchWhitehead Institute for Biomedical ResearchDepartment of Biological Engineering, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of TechnologyDepartment of Microbiology, Harvard Medical SchoolJohn A. Paulson School of Engineering and Applied Sciences, Harvard UniversityWhitehead Institute for Biomedical ResearchAbstract Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here, we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly SMCs, are a susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterize the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, PCs, and ECs. We observe that infected SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we show human ECs exposed to the secretome of infected SMCs produce hemostatic factors that contribute to vascular dysfunction despite not being susceptible to direct infection. The findings here recapitulate observations from patient sera in human COVID-19 patients and provide mechanistic insight into the unique vascular implications of SARS-CoV-2 infection at a cellular level.https://doi.org/10.1038/s41467-024-54917-4 |
| spellingShingle | Alexsia Richards Andrew S. Khalil Max Friesen Troy W. Whitfield Xinlei Gao Tenzin Lungjangwa Roger D. Kamm Zhengpeng Wan Lee Gehrke David Mooney Rudolf Jaenisch SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection Nature Communications |
| title | SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection |
| title_full | SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection |
| title_fullStr | SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection |
| title_full_unstemmed | SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection |
| title_short | SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection |
| title_sort | sars cov 2 infection of human pluripotent stem cell derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection |
| url | https://doi.org/10.1038/s41467-024-54917-4 |
| work_keys_str_mv | AT alexsiarichards sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT andrewskhalil sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT maxfriesen sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT troywwhitfield sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT xinleigao sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT tenzinlungjangwa sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT rogerdkamm sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT zhengpengwan sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT leegehrke sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT davidmooney sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection AT rudolfjaenisch sarscov2infectionofhumanpluripotentstemcellderivedvascularcellsrevealssmoothmusclecellsaskeymediatorsofvascularpathologyduringinfection |