Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:119 |
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| Enthalten in: |
Cardiovascular research - 119(2023), 1 vom: 17. März, Seite 155-166 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Egea, Virginia [VerfasserIn] |
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| Links: |
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| Themen: |
Atheroma |
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| Anmerkungen: |
Date Completed 21.03.2023 Date Revised 23.03.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/cvr/cvac022 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337695903 |
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| 100 | 1 | |a Egea, Virginia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 23.03.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Atheroma | |
| 650 | 4 | |a Chemotaxis | |
| 650 | 4 | |a MMPs | |
| 650 | 4 | |a MSC | |
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| 650 | 7 | |a Immunologic Factors |2 NLM | |
| 700 | 1 | |a Megens, Remco Theodorus Adrianus |e verfasserin |4 aut | |
| 700 | 1 | |a Santovito, Donato |e verfasserin |4 aut | |
| 700 | 1 | |a Wantha, Sarawuth |e verfasserin |4 aut | |
| 700 | 1 | |a Brandl, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Siess, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Khani, Sajjad |e verfasserin |4 aut | |
| 700 | 1 | |a Soehnlein, Oliver |e verfasserin |4 aut | |
| 700 | 1 | |a Bartelt, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Weber, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Ries, Christian |e verfasserin |4 aut | |
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