Communications<\/span><\/em><\/a>\u00a0on December 30, Jaenisch, postdoc in his lab Alexsia Richards, Harvard University Professor and Wyss Institute for Biologically Inspired Engineering Member David Mooney, and then-postdoc in the Jaenisch and Mooney labs Andrew Khalil share their findings and present a scalable stem cell-derived model system with which to study vascular cell biology and test medical therapies.<\/p>\nA new problem requires a new approach<\/h2>\n
When the COVID-19 pandemic began, Richards, a virologist, quickly pivoted her focus to SARS-CoV-2. Khalil, a bioengineer, had already been working on a new approach to generate vascular cells. The researchers realized that a collaboration could provide Richards with the research tool she needed and Khalil with an important research question to which his tool could be applied.<\/p>\n
The three cell types that Khalil\u2019s approach generated were endothelial cells, the vascular cells that form the lining of blood vessels; and smooth muscle cells and pericytes, perivascular cells that surround blood vessels and provide them with structure and maintenance, among other functions. Khalil\u2019s biggest innovation was to generate all three cell types in the same media\u2014the mixture of nutrients and signaling molecules in which stem cell-derived cells are grown.<\/p>\n
The combination of signals in the media determines the final cell type into which a stem cell will mature, so it is much easier to grow each cell type separately in specially tailored media than to find a mixture that works for all three. Typically, Richards explains, virologists will generate a desired cell type using the easiest method, which means growing each cell type and then observing the effects of viral infection on it in isolation. However, this approach can limit results in several ways. Firstly, it can make it challenging to distinguish the differences in how cell types react to a virus from the differences caused by the cells being grown in different media.<\/p>\n
\u201cBy making these cells under identical conditions, we could see in much higher resolution the effects of the virus on these different cell populations, and that was essential in order to form a strong hypothesis of the mechanisms of vascular symptom risk and progression,\u201d Khalil says.<\/p>\n
Secondly, infecting isolated cell types with a virus does not accurately represent what happens in the body, where cells are in constant communication as they react to viral exposure. Indeed, Richards\u2019 and Khalil\u2019s work ultimately revealed that the communication between infected and uninfected cell types plays a critical role in the vascular effects of COVID-19.<\/p>\n
\u201cThe field of virology often overlooks the importance of considering how cells influence other cells and designing models to reflect that,\u201d Richards says. \u201cCells do not get infected in isolation, and the value of our model is that it allows us to observe what\u2019s happening between cells during infection.\u201d<\/p>\n
Viral infection of smooth muscle cells has broader, indirect effects<\/h2>\n
When the researchers exposed their cells to SARS-CoV-2, the smooth muscle cells and pericytes became infected\u2014the former at especially high levels, and this infection resulted in strong inflammatory gene expression\u2014but the endothelial cells resisted infection. Endothelial cells did show some response to viral exposure, likely due to interactions with proteins on the virus\u2019 surface. Typically, endothelial cells press tightly together to form a firm barrier that keeps blood inside of blood vessels and prevents viruses from getting out. When exposed to SARS-CoV-2, the junctions between endothelial cells appeared to weaken slightly. The cells also had increased levels of reactive oxygen species, which are damaging byproducts of certain cellular processes.<\/p>\n
However, big changes in endothelial cells only occurred after the cells were exposed to infected smooth muscle cells. This triggered high levels of inflammatory signaling within the endothelial cells. It led to changes in the expression of many genes relevant to immune response. Some of the genes affected were involved in coagulation pathways, which thicken blood and so can cause blood clots and related vascular events. The junctions between endothelial cells experienced much more significant weakening after exposure to infected smooth muscle cells, which would lead to blood leakage and viral spread. All of these changes occurred without SARS-CoV-2 ever infecting the endothelial cells.<\/p>\n
This work shows that viral infection of smooth muscle cells, and their resultant signaling to endothelial cells, is the lynchpin in the vascular damage caused by SARS-CoV-2. This would not have been apparent if the researchers had not been able to observe the cells interacting with each other.<\/p>\n
Clinical relevance of stem cell results<\/h2>\n
The effects that the researchers observed were consistent with patient data. Some of the genes whose expression changed in their stem cell-derived model had been identified as markers of high risk for vascular complications in COVID-19 patients with severe infections. Additionally, the researchers found that a later strain of SARS-CoV-2, an Omicron variant, had much weaker effects on the vascular and perivascular cells than did the original viral strain. This is consistent with the reduced levels of vascular complications seen in COVID-19 patients infected with recent strains.<\/p>\n
Having identified smooth muscle cells as the main site of SARS-Cov-2 infection in the vascular system, the researchers next used their model system to test one drug\u2019s ability to prevent infection of smooth muscle cells. They found that the drug, N, N-Dimethyl-D-erythro-sphingosine, could reduce infection of the cell type without harming smooth muscle or endothelial cells. Although preventing vascular complications of COVID-19 is not as pressing a need with current viral strains, the researchers see this experiment as proof that their stem cell model could be used for future drug development. New coronaviruses and other pathogens are frequently evolving, and when a future virus causes vascular complications, this model could be used to quickly test drugs to find potential therapies while the need is still high. The model system could also be used to answer other questions about vascular cells, how these cells interact, and how they respond to viruses.<\/p>\n
\u201cBy integrating bioengineering strategies into the analysis of a fundamental question in viral pathology, we addressed important practical challenges in modeling human disease in culture and gained new insights into SARS-CoV-2 infection,\u201d Mooney says.<\/p>\n
\u201cOur interdisciplinary approach allowed us to develop an improved stem cell model for infection of the vasculature,\u201d says Jaenisch, who is also a professor of biology at the Massachusetts Institute of Technology. \u201cOur lab is already applying this model to other questions of interest, and we hope that it can be a valuable tool for other researchers.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"
COVID-19 is a respiratory disease primarily affecting the lungs. However, the SARS-CoV-2 virus that causes COVID-19 surprised doctors and scientists by triggering an unusually large percentage of patients to experience vascular complications \u2013 issues related to blood flow, such as blood clots, heart attacks, and strokes. Whitehead Institute Founding Member Rudolf Jaenisch and colleagues wanted […]<\/p>\n","protected":false},"author":1783,"featured_media":30721,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[6212,6240,6221],"tags":[],"class_list":["post-30720","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news-briefs","category-whitehead-institute-faculty-locations","category-whitehead-institute","placement-placement-homepage","research-area-human-disease","research-area-neurobiology","research-area-stem-cell-and-developmental-biology"],"acf":[],"yoast_head":"\n
Cellular interactions help explain vascular complications due to COVID-19 virus infection - MIT Department of Biology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Cellular interactions help explain vascular complications due to COVID-19 virus infection\" \/>\n<meta property=\"og:description\" content=\"COVID-19 is a respiratory disease primarily affecting the lungs. However, the SARS-CoV-2 virus that causes COVID-19 surprised doctors and scientists by triggering an unusually large percentage of patients to experience vascular complications \u2013 issues related to blood flow, such as blood clots, heart attacks, and strokes. Whitehead Institute Founding Member Rudolf Jaenisch and colleagues wanted […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/\" \/>\n<meta property=\"og:site_name\" content=\"MIT Department of Biology\" \/>\n<meta property=\"article:published_time\" content=\"2025-01-06T18:28:52+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png\" \/>\n\t<meta property=\"og:image:width\" content=\"375\" \/>\n\t<meta property=\"og:image:height\" content=\"250\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/png\" \/>\n<meta name=\"author\" content=\"Lillian Eden\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Lillian Eden\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"6 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/\",\"url\":\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/\",\"name\":\"Cellular interactions help explain vascular complications due to COVID-19 virus infection - MIT Department of Biology\",\"isPartOf\":{\"@id\":\"https:\/\/biology.mit.edu\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#primaryimage\"},\"image\":{\"@id\":\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png\",\"datePublished\":\"2025-01-06T18:28:52+00:00\",\"dateModified\":\"2025-01-06T18:28:52+00:00\",\"author\":{\"@id\":\"https:\/\/biology.mit.edu\/#\/schema\/person\/3d5c8c331d23c8d05f9468e1dc85b914\"},\"breadcrumb\":{\"@id\":\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#primaryimage\",\"url\":\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png\",\"contentUrl\":\"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png\",\"width\":375,\"height\":250,\"caption\":\"A human pluripotent stem cell-derived smooth muscle cell infected with the virus SARS-Cov-2. Sites of viral genome replication are in green. Credit Alexsia Richards\/Whitehead Institute\"},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\/\/biology.mit.edu\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Cellular interactions help explain vascular complications due to COVID-19 virus infection\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\/\/biology.mit.edu\/#website\",\"url\":\"https:\/\/biology.mit.edu\/\",\"name\":\"MIT Department of Biology\",\"description\":\"\",\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\/\/biology.mit.edu\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"en-US\"},{\"@type\":\"Person\",\"@id\":\"https:\/\/biology.mit.edu\/#\/schema\/person\/3d5c8c331d23c8d05f9468e1dc85b914\",\"name\":\"Lillian Eden\",\"image\":{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\/\/biology.mit.edu\/#\/schema\/person\/image\/\",\"url\":\"https:\/\/secure.gravatar.com\/avatar\/8b9f5f4de4b70b8649adb004b00aae0b?s=96&d=mm&r=g\",\"contentUrl\":\"https:\/\/secure.gravatar.com\/avatar\/8b9f5f4de4b70b8649adb004b00aae0b?s=96&d=mm&r=g\",\"caption\":\"Lillian Eden\"},\"url\":\"https:\/\/biology.mit.edu\/author\/leden\/\"}]}<\/script>\n","yoast_head_json":{"title":"Cellular interactions help explain vascular complications due to COVID-19 virus infection - MIT Department of Biology","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/","og_locale":"en_US","og_type":"article","og_title":"Cellular interactions help explain vascular complications due to COVID-19 virus infection","og_description":"COVID-19 is a respiratory disease primarily affecting the lungs. However, the SARS-CoV-2 virus that causes COVID-19 surprised doctors and scientists by triggering an unusually large percentage of patients to experience vascular complications \u2013 issues related to blood flow, such as blood clots, heart attacks, and strokes. Whitehead Institute Founding Member Rudolf Jaenisch and colleagues wanted […]","og_url":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/","og_site_name":"MIT Department of Biology","article_published_time":"2025-01-06T18:28:52+00:00","og_image":[{"width":375,"height":250,"url":"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png","type":"image\/png"}],"author":"Lillian Eden","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Lillian Eden","Est. reading time":"6 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"WebPage","@id":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/","url":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/","name":"Cellular interactions help explain vascular complications due to COVID-19 virus infection - MIT Department of Biology","isPartOf":{"@id":"https:\/\/biology.mit.edu\/#website"},"primaryImageOfPage":{"@id":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#primaryimage"},"image":{"@id":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#primaryimage"},"thumbnailUrl":"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png","datePublished":"2025-01-06T18:28:52+00:00","dateModified":"2025-01-06T18:28:52+00:00","author":{"@id":"https:\/\/biology.mit.edu\/#\/schema\/person\/3d5c8c331d23c8d05f9468e1dc85b914"},"breadcrumb":{"@id":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/"]}]},{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#primaryimage","url":"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png","contentUrl":"https:\/\/biology.mit.edu\/wp-content\/uploads\/2025\/01\/SMC-with-COVID.png","width":375,"height":250,"caption":"A human pluripotent stem cell-derived smooth muscle cell infected with the virus SARS-Cov-2. Sites of viral genome replication are in green. Credit Alexsia Richards\/Whitehead Institute"},{"@type":"BreadcrumbList","@id":"https:\/\/biology.mit.edu\/cellular-interactions-help-explain-vascular-complications-due-to-covid-19-virus-infection\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/biology.mit.edu\/"},{"@type":"ListItem","position":2,"name":"Cellular interactions help explain vascular complications due to COVID-19 virus infection"}]},{"@type":"WebSite","@id":"https:\/\/biology.mit.edu\/#website","url":"https:\/\/biology.mit.edu\/","name":"MIT Department of Biology","description":"","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/biology.mit.edu\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"},{"@type":"Person","@id":"https:\/\/biology.mit.edu\/#\/schema\/person\/3d5c8c331d23c8d05f9468e1dc85b914","name":"Lillian Eden","image":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/biology.mit.edu\/#\/schema\/person\/image\/","url":"https:\/\/secure.gravatar.com\/avatar\/8b9f5f4de4b70b8649adb004b00aae0b?s=96&d=mm&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/8b9f5f4de4b70b8649adb004b00aae0b?s=96&d=mm&r=g","caption":"Lillian Eden"},"url":"https:\/\/biology.mit.edu\/author\/leden\/"}]}},"_links":{"self":[{"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/posts\/30720","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/users\/1783"}],"replies":[{"embeddable":true,"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/comments?post=30720"}],"version-history":[{"count":1,"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/posts\/30720\/revisions"}],"predecessor-version":[{"id":30722,"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/posts\/30720\/revisions\/30722"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/media\/30721"}],"wp:attachment":[{"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/media?parent=30720"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/categories?post=30720"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biology.mit.edu\/wp-json\/wp\/v2\/tags?post=30720"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}