Coordination of endothelial cell positioning and fate specification by the epicardium
The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA...
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creator | Quijada, Pearl Trembley, Michael A. Misra, Adwiteeya Myers, Jacquelyn A. Baker, Cameron D. Pérez-Hernández, Marta Myers, Jason R. Dirkx, Ronald A. Cohen, Ethan David Delmar, Mario Ashton, John M. Small, Eric M. |
description | The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.
It remains unclear how spatial information controls endothelial cell identity and behavior in the developing heart. Here the authors perform single cell RNA sequencing at key developmental timepoints in mice to interrogate cellular contributions to coronary vessel patterning and maturation in the epicardium. |
doi_str_mv | 10.1038/s41467-021-24414-z |
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It remains unclear how spatial information controls endothelial cell identity and behavior in the developing heart. Here the authors perform single cell RNA sequencing at key developmental timepoints in mice to interrogate cellular contributions to coronary vessel patterning and maturation in the epicardium.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-021-24414-z</identifier><identifier>PMID: 34230480</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 14 ; 14/1 ; 38 ; 38/32 ; 38/39 ; 38/91 ; 631/114/2404 ; 631/136/16/1986 ; 631/136/2086/2176 ; 631/1647/334/1874/345 ; 631/337/2019 ; 64 ; 64/110 ; Angiogenesis ; Blood vessels ; Chemokines ; Coronary vessels ; Embryos ; Endothelial cells ; Epicardium ; Gene sequencing ; Heart ; Humanities and Social Sciences ; Localization ; Maturation ; Mesenchyme ; Mesothelium ; multidisciplinary ; Paracrine signalling ; Pattern formation ; Science ; Science (multidisciplinary) ; Signaling ; Spatial data ; Specifications ; Transcription factors</subject><ispartof>Nature communications, 2021-07, Vol.12 (1), p.4155-4155, Article 4155</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c583t-1120de0adf7f16d5df19008a46d396305a09d793336324abce007a30dfde09d63</citedby><cites>FETCH-LOGICAL-c583t-1120de0adf7f16d5df19008a46d396305a09d793336324abce007a30dfde09d63</cites><orcidid>0000-0001-6119-103X ; 0000-0002-3792-4317 ; 0000-0003-2477-2374 ; 0000-0001-9875-5994 ; 0000-0001-8593-0343 ; 0000-0002-5005-028X</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/PMC8260743/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260743/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,27924,27925,41120,42189,51576,53791,53793</link.rule.ids></links><search><creatorcontrib>Quijada, Pearl</creatorcontrib><creatorcontrib>Trembley, Michael A.</creatorcontrib><creatorcontrib>Misra, Adwiteeya</creatorcontrib><creatorcontrib>Myers, Jacquelyn A.</creatorcontrib><creatorcontrib>Baker, Cameron D.</creatorcontrib><creatorcontrib>Pérez-Hernández, Marta</creatorcontrib><creatorcontrib>Myers, Jason R.</creatorcontrib><creatorcontrib>Dirkx, Ronald A.</creatorcontrib><creatorcontrib>Cohen, Ethan David</creatorcontrib><creatorcontrib>Delmar, Mario</creatorcontrib><creatorcontrib>Ashton, John M.</creatorcontrib><creatorcontrib>Small, Eric M.</creatorcontrib><title>Coordination of endothelial cell positioning and fate specification by the epicardium</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><description>The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.
It remains unclear how spatial information controls endothelial cell identity and behavior in the developing heart. Here the authors perform single cell RNA sequencing at key developmental timepoints in mice to interrogate cellular contributions to coronary vessel patterning and maturation in the epicardium.</description><subject>13</subject><subject>14</subject><subject>14/1</subject><subject>38</subject><subject>38/32</subject><subject>38/39</subject><subject>38/91</subject><subject>631/114/2404</subject><subject>631/136/16/1986</subject><subject>631/136/2086/2176</subject><subject>631/1647/334/1874/345</subject><subject>631/337/2019</subject><subject>64</subject><subject>64/110</subject><subject>Angiogenesis</subject><subject>Blood vessels</subject><subject>Chemokines</subject><subject>Coronary vessels</subject><subject>Embryos</subject><subject>Endothelial cells</subject><subject>Epicardium</subject><subject>Gene sequencing</subject><subject>Heart</subject><subject>Humanities and Social 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A.</au><au>Baker, Cameron D.</au><au>Pérez-Hernández, Marta</au><au>Myers, Jason R.</au><au>Dirkx, Ronald A.</au><au>Cohen, Ethan David</au><au>Delmar, Mario</au><au>Ashton, John M.</au><au>Small, Eric M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Coordination of endothelial cell positioning and fate specification by the epicardium</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><date>2021-07-06</date><risdate>2021</risdate><volume>12</volume><issue>1</issue><spage>4155</spage><epage>4155</epage><pages>4155-4155</pages><artnum>4155</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.
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title | Coordination of endothelial cell positioning and fate specification by the epicardium |
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