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Review 1: "SARS-CoV-2 Infection of Human Pluripotent Stem Cell-derived Vascular Cells Reveals Smooth Muscle Cells as Key Mediators of Vascular Pathology during Infection"

While considering the model valuable, the reviewer suggested improvements, including updating the literature review, comparing with other models, validating protocols, and deepening pathway analysis.

Published onJul 02, 2024
Review 1: "SARS-CoV-2 Infection of Human Pluripotent Stem Cell-derived Vascular Cells Reveals Smooth Muscle Cells as Key Mediators of Vascular Pathology during Infection"
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SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection
SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection
Description

Summary 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 events1. This prothrombotic state is considered a key factor in the increased risk of stroke, which has been observed clinically during both acute infection and long after symptoms have cleared2. Here we developed a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells, pericytes, and smooth muscle cells to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly smooth muscle cells (SMCs), are a specifically susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterized the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, and endothelial cells (ECs). We observed that infected human SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we showed human ECs exposed to the secretome of infected SMCs produce hemostatic factors that can 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.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: In the manuscript titled “SARS-CoV-2 Infection of Human Pluripotent Stem Cell-Derived Vascular Cells Highlights Smooth Muscle Cells as Principal Contributors to Vascular Pathology During Infection”, the authors established a model using human-induced pluripotent stem cell-derived endothelial cells, pericytes, and smooth muscle cells to emulate the vascular pathology observed with SARS-CoV-2 exposure. The findings underscore that, among perivascular cells, smooth muscle cells (SMCs) are particularly vulnerable to SARS-CoV-2. Through RNA sequencing, the authors delineated the transcriptomic alterations following SARS-CoV-2 infection in both SMCs and endothelial cells (ECs). It was evident that SMCs, upon infection, adopt a pro-inflammatory phenotype and amplify the expression of pivotal players in the coagulation process. Moreover, it was revealed that ECs, when exposed to secreted factors from infected SMCs, generate hemostatic components potentially leading to vascular dysfunction, even though they remain impervious to direct viral infection. These observations resonate with patterns seen in serum samples from COVID-19 patients, offering a deeper understanding of the distinctive vascular consequences of SARS-CoV-2 infection at a cellular dimension. The infection model is of interest to the field. However, some points remain to be addressed:

  1. The background and discussion of the manuscript requires updating to keep up with the rapidly evolving progress in the field of SARS-CoV-2 research.

  2. How does the model used in this study compare, in terms of advantages and disadvantages, to other in vivo and in vitro SARS-CoV-2 research models? A comprehensive summary and comparison would be beneficial.

  3. To validate if the cell differentiation protocol's efficiency and outcome are consistent when starting from different pluripotent stem cell lines or induced pluripotent stem cells derived from various sources.

  4. It would be beneficial to compare the derived cells' behavior and/or gene expression profiles with primary cells from tissues. This comparison would give insights into how closely the derived cells mimic in vivo counterparts.

  5. The gene set enrichment analysis provides a broad overview of the cellular pathways affected. It would be helpful to analyze the most significantly affected pathways in detail, discussing their relevance and potential implications in the context of COVID-19 disease. Do the in vivo cells also mirror the trends observed in the in vitro model? And if so, how closely do their identities align?

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