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Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome

Salvatore Vaiasicca, Gianmarco Melone, David W. James, Marcos Quintela, Alessandra Preziuso, Richard H. Finnell, Steve Conlan Orcid Logo, Lewis W. Francis, Bruna Corradetti Orcid Logo

Stem Cell Research and Therapy, Volume: 14, Issue: 1

Swansea University Author: Steve Conlan Orcid Logo

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DOI (Published version): 10.1186/s13287-023-03503-4

Abstract

Background: Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more comple...

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Published in: Stem Cell Research and Therapy
ISSN: 1757-6512
Published: Springer Science and Business Media LLC 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa64628
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Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity. Methods: Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were carried out to confirm the biological processes identified as enriched in DS-CV compared to CV (i.e., cell cycle, proliferation features, immunosuppression and ROS production). Results: Genes located on chromosomes other than the canonical 21 (Ch. 2, 6 and 22) are responsible for the impairment of life-essential pathways, including cell cycle regulation, innate immune response and reaction to external stimuli were found to be differentially expressed in DS-CV. Experimental validation confirmed the key role of the biological pathways regulated by those genes in the etiology of such a multisystem condition. 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spelling v2 64628 2023-09-27 Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 2023-09-27 BMS Background: Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity. Methods: Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were carried out to confirm the biological processes identified as enriched in DS-CV compared to CV (i.e., cell cycle, proliferation features, immunosuppression and ROS production). Results: Genes located on chromosomes other than the canonical 21 (Ch. 2, 6 and 22) are responsible for the impairment of life-essential pathways, including cell cycle regulation, innate immune response and reaction to external stimuli were found to be differentially expressed in DS-CV. Experimental validation confirmed the key role of the biological pathways regulated by those genes in the etiology of such a multisystem condition. Conclusions: NGS dataset generated in this study highlights the compromised functionality in the proliferative rate and in the innate response of DS-associated clinical conditions and identifies DS-CV as suitable tools for the development of specifically tailored, personalized intervention modalities. Journal Article Stem Cell Research and Therapy 14 1 Springer Science and Business Media LLC 1757-6512 Chorionic villi, Mesenchymal stem cells, Down syndrome, Next-generation sequencing analysis 23 9 2023 2023-09-23 10.1186/s13287-023-03503-4 http://dx.doi.org/10.1186/s13287-023-03503-4 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University B.C. received salary support from the Sêr Cymru II program, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF) and Houston Methodist Research Institute (USA). 2024-01-08T14:11:13.5271208 2023-09-27T14:31:17.3564848 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Salvatore Vaiasicca 1 Gianmarco Melone 2 David W. James 3 Marcos Quintela 4 Alessandra Preziuso 5 Richard H. Finnell 6 Steve Conlan 0000-0002-2562-3461 7 Lewis W. Francis 8 Bruna Corradetti 0000-0002-0345-4847 9 64628__28838__edd994b2a77a45ab800cbe2eb1a7a286.pdf 64628.VOR.pdf 2023-10-19T16:05:45.4845009 Output 3562523 application/pdf Version of Record true © The Author(s) 2023. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
spellingShingle Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Steve Conlan
title_short Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
title_full Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
title_fullStr Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
title_full_unstemmed Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
title_sort Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
author_id_str_mv 0bb6bd247e32fb4249de62c0013b51cb
author_id_fullname_str_mv 0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
author Steve Conlan
author2 Salvatore Vaiasicca
Gianmarco Melone
David W. James
Marcos Quintela
Alessandra Preziuso
Richard H. Finnell
Steve Conlan
Lewis W. Francis
Bruna Corradetti
format Journal article
container_title Stem Cell Research and Therapy
container_volume 14
container_issue 1
publishDate 2023
institution Swansea University
issn 1757-6512
doi_str_mv 10.1186/s13287-023-03503-4
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://dx.doi.org/10.1186/s13287-023-03503-4
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description Background: Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity. Methods: Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were carried out to confirm the biological processes identified as enriched in DS-CV compared to CV (i.e., cell cycle, proliferation features, immunosuppression and ROS production). Results: Genes located on chromosomes other than the canonical 21 (Ch. 2, 6 and 22) are responsible for the impairment of life-essential pathways, including cell cycle regulation, innate immune response and reaction to external stimuli were found to be differentially expressed in DS-CV. Experimental validation confirmed the key role of the biological pathways regulated by those genes in the etiology of such a multisystem condition. Conclusions: NGS dataset generated in this study highlights the compromised functionality in the proliferative rate and in the innate response of DS-associated clinical conditions and identifies DS-CV as suitable tools for the development of specifically tailored, personalized intervention modalities.
published_date 2023-09-23T14:11:14Z
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