Cargando…
Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques
AIMS: Atherosclerosis is a chronic inflammatory disease of the arteries leading to the formation of atheromatous plaques. Human mesenchymal stem cells (hMSCs) are recruited from the circulation into plaques where in response to their environment they adopt a phenotype with immunomodulatory propertie...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022860/ https://www.ncbi.nlm.nih.gov/pubmed/35238350 http://dx.doi.org/10.1093/cvr/cvac022 |
_version_ | 1784908810359406592 |
---|---|
author | Egea, Virginia Megens, Remco Theodorus Adrianus Santovito, Donato Wantha, Sarawuth Brandl, Richard Siess, Wolfgang Khani, Sajjad Soehnlein, Oliver Bartelt, Alexander Weber, Christian Ries, Christian |
author_facet | Egea, Virginia Megens, Remco Theodorus Adrianus Santovito, Donato Wantha, Sarawuth Brandl, Richard Siess, Wolfgang Khani, Sajjad Soehnlein, Oliver Bartelt, Alexander Weber, Christian Ries, Christian |
author_sort | Egea, Virginia |
collection | PubMed |
description | AIMS: Atherosclerosis is a chronic inflammatory disease of the arteries leading to the formation of atheromatous plaques. Human mesenchymal stem cells (hMSCs) are recruited from the circulation into plaques where in response to their environment they adopt a phenotype with immunomodulatory properties. However, the mechanisms underlying hMSC function in these processes are unclear. Recently, we described that miRNA let-7f controls hMSC invasion guided by inflammatory cytokines and chemokines. Here, we investigated the role of let-7f in hMSC tropism to human atheromas and the effects of the plaque microenvironment on cell fate and release of soluble factors. METHODS AND RESULTS: Incubation of hMSCs with LL-37, an antimicrobial peptide abundantly found in plaques, increased biosynthesis of let-7f and N-formyl peptide receptor 2 (FPR2), enabling chemotactic invasion of the cells towards LL-37, as determined by qRT-PCR, flow cytometry, and cell invasion assay analysis. In an Apoe(−/−) mouse model of atherosclerosis, circulating hMSCs preferentially adhered to athero-prone endothelium. This property was facilitated by elevated levels of let-7f in the hMSCs, as assayed by ex vivo artery perfusion and two-photon laser scanning microscopy. Exposure of hMSCs to homogenized human atheromatous plaque material considerably induced the production of various cytokines, chemokines, matrix metalloproteinases, and tissue inhibitors of metalloproteinases, as studied by PCR array and western blot analysis. Moreover, exposure to human plaque extracts elicited differentiation of hMSCs into cells of the myogenic lineage, suggesting a potentially plaque-stabilizing effect. CONCLUSIONS: Our findings indicate that let-7f promotes hMSC tropism towards atheromas through the LL-37/FPR2 axis and demonstrate that hMSCs upon contact with human plaque environment develop a potentially athero-protective signature impacting the pathophysiology of atherosclerosis. |
format | Online Article Text |
id | pubmed-10022860 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-100228602023-03-18 Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques Egea, Virginia Megens, Remco Theodorus Adrianus Santovito, Donato Wantha, Sarawuth Brandl, Richard Siess, Wolfgang Khani, Sajjad Soehnlein, Oliver Bartelt, Alexander Weber, Christian Ries, Christian Cardiovasc Res Original Article AIMS: Atherosclerosis is a chronic inflammatory disease of the arteries leading to the formation of atheromatous plaques. Human mesenchymal stem cells (hMSCs) are recruited from the circulation into plaques where in response to their environment they adopt a phenotype with immunomodulatory properties. However, the mechanisms underlying hMSC function in these processes are unclear. Recently, we described that miRNA let-7f controls hMSC invasion guided by inflammatory cytokines and chemokines. Here, we investigated the role of let-7f in hMSC tropism to human atheromas and the effects of the plaque microenvironment on cell fate and release of soluble factors. METHODS AND RESULTS: Incubation of hMSCs with LL-37, an antimicrobial peptide abundantly found in plaques, increased biosynthesis of let-7f and N-formyl peptide receptor 2 (FPR2), enabling chemotactic invasion of the cells towards LL-37, as determined by qRT-PCR, flow cytometry, and cell invasion assay analysis. In an Apoe(−/−) mouse model of atherosclerosis, circulating hMSCs preferentially adhered to athero-prone endothelium. This property was facilitated by elevated levels of let-7f in the hMSCs, as assayed by ex vivo artery perfusion and two-photon laser scanning microscopy. Exposure of hMSCs to homogenized human atheromatous plaque material considerably induced the production of various cytokines, chemokines, matrix metalloproteinases, and tissue inhibitors of metalloproteinases, as studied by PCR array and western blot analysis. Moreover, exposure to human plaque extracts elicited differentiation of hMSCs into cells of the myogenic lineage, suggesting a potentially plaque-stabilizing effect. CONCLUSIONS: Our findings indicate that let-7f promotes hMSC tropism towards atheromas through the LL-37/FPR2 axis and demonstrate that hMSCs upon contact with human plaque environment develop a potentially athero-protective signature impacting the pathophysiology of atherosclerosis. Oxford University Press 2022-03-03 /pmc/articles/PMC10022860/ /pubmed/35238350 http://dx.doi.org/10.1093/cvr/cvac022 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Egea, Virginia Megens, Remco Theodorus Adrianus Santovito, Donato Wantha, Sarawuth Brandl, Richard Siess, Wolfgang Khani, Sajjad Soehnlein, Oliver Bartelt, Alexander Weber, Christian Ries, Christian Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques |
title | Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques |
title_full | Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques |
title_fullStr | Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques |
title_full_unstemmed | Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques |
title_short | Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques |
title_sort | properties and fate of human mesenchymal stem cells upon mirna let-7f-promoted recruitment to atherosclerotic plaques |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022860/ https://www.ncbi.nlm.nih.gov/pubmed/35238350 http://dx.doi.org/10.1093/cvr/cvac022 |
work_keys_str_mv | AT egeavirginia propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT megensremcotheodorusadrianus propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT santovitodonato propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT wanthasarawuth propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT brandlrichard propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT siesswolfgang propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT khanisajjad propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT soehnleinoliver propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT barteltalexander propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT weberchristian propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques AT rieschristian propertiesandfateofhumanmesenchymalstemcellsuponmirnalet7fpromotedrecruitmenttoatheroscleroticplaques |