Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling
The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurys...
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creator | Dawson, Ashley Li, Yanming Li, Yang Ren, Pingping Vasquez, Hernan G Zhang, Chen Rebello, Kimberly R Ageedi, Waleed Azares, Alon R Mattar, Aladdein Burchett Sheppard, Mary Burchett Lu, Hong S Coselli, Joseph S Cassis, Lisa A Daugherty, Alan Shen, Ying H LeMaire, Scott A |
description | The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (
= 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (
= 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of
and
in SMCs, and an upregulation of
in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that
was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly
) and
genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of
, the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation. |
doi_str_mv | 10.3390/genes13010095 |
format | Article |
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= 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (
= 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of
and
in SMCs, and an upregulation of
in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that
was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly
) and
genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of
, the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation.</description><identifier>ISSN: 2073-4425</identifier><identifier>EISSN: 2073-4425</identifier><identifier>DOI: 10.3390/genes13010095</identifier><identifier>PMID: 35052435</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adult ; Antibodies ; Aortic Aneurysm, Thoracic - diagnosis ; Aortic Aneurysm, Thoracic - etiology ; Aortic Aneurysm, Thoracic - metabolism ; Aortic aneurysms ; Case-Control Studies ; Cell Differentiation ; Collagen (type I) ; Correlation analysis ; Endothelial cells ; Female ; Fibroblasts ; Gene expression ; Gene Expression Regulation ; Genomes ; Genomics ; Homeostasis ; Humans ; Localization ; Male ; Marfan syndrome ; Marfan Syndrome - complications ; Microscopy ; Mutation ; Quality control ; Quorum sensing ; Receptors, Transforming Growth Factor beta - genetics ; Receptors, Transforming Growth Factor beta - metabolism ; Signal Transduction ; Single-Cell Analysis ; Smad protein ; Smooth muscle ; Transforming Growth Factor beta - genetics ; Transforming Growth Factor beta - metabolism ; Transforming growth factor-b ; Transforming growth factor-b1 ; Young Adult</subject><ispartof>Genes, 2021-12, Vol.13 (1), p.95</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-c9254d69066fa6a1909ca8f1ec537d2e19b8ef0d19e0ee7fc5fc68da5232c6de3</citedby><cites>FETCH-LOGICAL-c415t-c9254d69066fa6a1909ca8f1ec537d2e19b8ef0d19e0ee7fc5fc68da5232c6de3</cites><orcidid>0000-0003-4119-115X ; 0000-0003-2093-3775 ; 0000-0002-0577-2558 ; 0000-0003-0026-8640 ; 0000-0002-8736-4266</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774900/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774900/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35052435$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dawson, Ashley</creatorcontrib><creatorcontrib>Li, Yanming</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Ren, Pingping</creatorcontrib><creatorcontrib>Vasquez, Hernan G</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Rebello, Kimberly R</creatorcontrib><creatorcontrib>Ageedi, Waleed</creatorcontrib><creatorcontrib>Azares, Alon R</creatorcontrib><creatorcontrib>Mattar, Aladdein Burchett</creatorcontrib><creatorcontrib>Sheppard, Mary Burchett</creatorcontrib><creatorcontrib>Lu, Hong S</creatorcontrib><creatorcontrib>Coselli, Joseph S</creatorcontrib><creatorcontrib>Cassis, Lisa A</creatorcontrib><creatorcontrib>Daugherty, Alan</creatorcontrib><creatorcontrib>Shen, Ying H</creatorcontrib><creatorcontrib>LeMaire, Scott A</creatorcontrib><title>Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling</title><title>Genes</title><addtitle>Genes (Basel)</addtitle><description>The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (
= 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (
= 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of
and
in SMCs, and an upregulation of
in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that
was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly
) and
genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of
, the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation.</description><subject>Adult</subject><subject>Antibodies</subject><subject>Aortic Aneurysm, Thoracic - diagnosis</subject><subject>Aortic Aneurysm, Thoracic - etiology</subject><subject>Aortic Aneurysm, Thoracic - metabolism</subject><subject>Aortic aneurysms</subject><subject>Case-Control Studies</subject><subject>Cell Differentiation</subject><subject>Collagen (type I)</subject><subject>Correlation analysis</subject><subject>Endothelial cells</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Localization</subject><subject>Male</subject><subject>Marfan syndrome</subject><subject>Marfan Syndrome - complications</subject><subject>Microscopy</subject><subject>Mutation</subject><subject>Quality control</subject><subject>Quorum sensing</subject><subject>Receptors, Transforming Growth Factor beta - genetics</subject><subject>Receptors, Transforming Growth Factor beta - metabolism</subject><subject>Signal Transduction</subject><subject>Single-Cell Analysis</subject><subject>Smad protein</subject><subject>Smooth muscle</subject><subject>Transforming Growth Factor beta - genetics</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Transforming growth factor-b</subject><subject>Transforming growth factor-b1</subject><subject>Young Adult</subject><issn>2073-4425</issn><issn>2073-4425</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkc9u1DAQxi0EolXpkSuyxIVLYGzHSXxBqhZakIpA7HK2XGe8dZXYxU4KeS0epM9ULy1Viy8ztn_65s9HyEsGb4VQ8G6LATMTwACUfEL2ObSiqmsunz7I98hhzhdQTg0cQD4ne0KC5LWQ--T32oftgNUKh4EeBTMs2WcaXclxTkseTXmOafKWbnzOM1If6DczeQxTpr_8dE6_mORMoOsl9CmOSL_jFZoh0w9LdnOwk49Flm5OjqvrP3Ttt-VWar4gz1yh8PAuHpAfxx83q0_V6deTz6uj08rWTE6VVVzWfaOgaZxpDFOgrOkcQytF23Nk6qxDBz1TCIits9LZpuuN5ILbpkdxQN7f6l7OZyP2tvSdzKAvkx9NWnQ0Xj_-Cf5cb-OV7tq2VgBF4M2dQIo_Z8yTHn22ZV0mYJyz5g3nvBO83aGv_0Mv4pzKvH8pxjvWyB1V3VI2xZwTuvtmGOidrfqRrYV_9XCCe_qfieIG0FOg7g</recordid><startdate>20211230</startdate><enddate>20211230</enddate><creator>Dawson, Ashley</creator><creator>Li, Yanming</creator><creator>Li, Yang</creator><creator>Ren, Pingping</creator><creator>Vasquez, Hernan G</creator><creator>Zhang, Chen</creator><creator>Rebello, Kimberly R</creator><creator>Ageedi, Waleed</creator><creator>Azares, Alon R</creator><creator>Mattar, Aladdein Burchett</creator><creator>Sheppard, Mary Burchett</creator><creator>Lu, Hong S</creator><creator>Coselli, Joseph S</creator><creator>Cassis, Lisa A</creator><creator>Daugherty, Alan</creator><creator>Shen, Ying H</creator><creator>LeMaire, Scott A</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4119-115X</orcidid><orcidid>https://orcid.org/0000-0003-2093-3775</orcidid><orcidid>https://orcid.org/0000-0002-0577-2558</orcidid><orcidid>https://orcid.org/0000-0003-0026-8640</orcidid><orcidid>https://orcid.org/0000-0002-8736-4266</orcidid></search><sort><creationdate>20211230</creationdate><title>Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling</title><author>Dawson, Ashley ; Li, Yanming ; Li, Yang ; Ren, Pingping ; Vasquez, Hernan G ; Zhang, Chen ; Rebello, Kimberly R ; Ageedi, Waleed ; Azares, Alon R ; Mattar, Aladdein Burchett ; Sheppard, Mary Burchett ; Lu, Hong S ; Coselli, Joseph S ; Cassis, Lisa A ; Daugherty, Alan ; Shen, Ying H ; LeMaire, Scott A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-c9254d69066fa6a1909ca8f1ec537d2e19b8ef0d19e0ee7fc5fc68da5232c6de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adult</topic><topic>Antibodies</topic><topic>Aortic Aneurysm, Thoracic - diagnosis</topic><topic>Aortic Aneurysm, Thoracic - etiology</topic><topic>Aortic Aneurysm, Thoracic - metabolism</topic><topic>Aortic aneurysms</topic><topic>Case-Control Studies</topic><topic>Cell Differentiation</topic><topic>Collagen (type I)</topic><topic>Correlation analysis</topic><topic>Endothelial cells</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Localization</topic><topic>Male</topic><topic>Marfan syndrome</topic><topic>Marfan Syndrome - complications</topic><topic>Microscopy</topic><topic>Mutation</topic><topic>Quality control</topic><topic>Quorum sensing</topic><topic>Receptors, Transforming Growth Factor beta - genetics</topic><topic>Receptors, Transforming Growth Factor beta - metabolism</topic><topic>Signal Transduction</topic><topic>Single-Cell Analysis</topic><topic>Smad protein</topic><topic>Smooth muscle</topic><topic>Transforming Growth Factor beta - genetics</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Transforming growth factor-b</topic><topic>Transforming growth factor-b1</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dawson, Ashley</creatorcontrib><creatorcontrib>Li, Yanming</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Ren, Pingping</creatorcontrib><creatorcontrib>Vasquez, Hernan G</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Rebello, Kimberly R</creatorcontrib><creatorcontrib>Ageedi, Waleed</creatorcontrib><creatorcontrib>Azares, Alon R</creatorcontrib><creatorcontrib>Mattar, Aladdein Burchett</creatorcontrib><creatorcontrib>Sheppard, Mary Burchett</creatorcontrib><creatorcontrib>Lu, Hong S</creatorcontrib><creatorcontrib>Coselli, Joseph S</creatorcontrib><creatorcontrib>Cassis, Lisa A</creatorcontrib><creatorcontrib>Daugherty, Alan</creatorcontrib><creatorcontrib>Shen, Ying H</creatorcontrib><creatorcontrib>LeMaire, Scott A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>Biological Sciences</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dawson, Ashley</au><au>Li, Yanming</au><au>Li, Yang</au><au>Ren, Pingping</au><au>Vasquez, Hernan G</au><au>Zhang, Chen</au><au>Rebello, Kimberly R</au><au>Ageedi, Waleed</au><au>Azares, Alon R</au><au>Mattar, Aladdein Burchett</au><au>Sheppard, Mary Burchett</au><au>Lu, Hong S</au><au>Coselli, Joseph S</au><au>Cassis, Lisa A</au><au>Daugherty, Alan</au><au>Shen, Ying H</au><au>LeMaire, Scott A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling</atitle><jtitle>Genes</jtitle><addtitle>Genes (Basel)</addtitle><date>2021-12-30</date><risdate>2021</risdate><volume>13</volume><issue>1</issue><spage>95</spage><pages>95-</pages><issn>2073-4425</issn><eissn>2073-4425</eissn><abstract>The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (
= 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (
= 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of
and
in SMCs, and an upregulation of
in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that
was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly
) and
genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of
, the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>35052435</pmid><doi>10.3390/genes13010095</doi><orcidid>https://orcid.org/0000-0003-4119-115X</orcidid><orcidid>https://orcid.org/0000-0003-2093-3775</orcidid><orcidid>https://orcid.org/0000-0002-0577-2558</orcidid><orcidid>https://orcid.org/0000-0003-0026-8640</orcidid><orcidid>https://orcid.org/0000-0002-8736-4266</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adult Antibodies Aortic Aneurysm, Thoracic - diagnosis Aortic Aneurysm, Thoracic - etiology Aortic Aneurysm, Thoracic - metabolism Aortic aneurysms Case-Control Studies Cell Differentiation Collagen (type I) Correlation analysis Endothelial cells Female Fibroblasts Gene expression Gene Expression Regulation Genomes Genomics Homeostasis Humans Localization Male Marfan syndrome Marfan Syndrome - complications Microscopy Mutation Quality control Quorum sensing Receptors, Transforming Growth Factor beta - genetics Receptors, Transforming Growth Factor beta - metabolism Signal Transduction Single-Cell Analysis Smad protein Smooth muscle Transforming Growth Factor beta - genetics Transforming Growth Factor beta - metabolism Transforming growth factor-b Transforming growth factor-b1 Young Adult |
title | Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling |
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