Human Vascular Wall Mesenchymal Stromal Cells Contribute to Abdominal Aortic Aneurysm Pathogenesis Through an Impaired Immunomodulatory Activity and Increased Levels of Matrix Metalloproteinase-9

Ciavarella, Carmen; Alviano, Francesco; Gallitto, Enrico; Ricci, Francesca; Buzzi, Marina; Velati, Claudio; Stella, Andréa; Freyrie, Antonio; Pasquinelli, Gianandrea

doi:10.1253/circj.cj-14-0857

Cited by 27 publications

(33 citation statements)

References 29 publications

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“…A work by our team described functional abnormalities on a human model of MSCs derived from patients affected by AAA (AAA-MSCs). Consistent with the AAA pathogenesis, AAA-MSCs displayed significant hyper-expression of matrix metalloproteinases (MMPs), especially MMP-9, whereas the reduced release of anti-inflammatory mediators resulted in a weak immunosuppressive effect of AAA-MSCs on activated peripheral blood mononuclear cells (PBMCs) [15]. Vascular remodelling and inflammatory process are tightly connected, because inflammatory mediators stimulate the MMP expression in different biological contexts [16–18]; moreover, a relation has been demonstrated between MMP-mediated elastin degradation and occurrence of calcification in a rat model of AAA [19].…”

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confidence: 99%

The crosstalk between vascular MSCs and inflammatory mediators determines the pro-calcific remodelling of human atherosclerotic aneurysm

et al. 2017

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BackgroundHuman mesenchymal stem cells (MSCs) possess well-known reparative abilities, but any defect of the immunomodulatory activity and/or the differentiation process may determine the development of human diseases, including those affecting the vascular wall. MSCs residing within the human aortic wall represent a potential cell mediator of atherosclerotic aneurysm development.MethodsMSCs isolated from healthy and aneurysm aortas were characterized by flow cytometer and tested for differentiation properties. Healthy aorta (ha)-MSCs were then subjected to inflammatory stimuli to evaluate the microenvironmental impact on their function and involvement in vascular remodelling.ResultsAbdominal aortic aneurysm (AAA)-MSCs were isolated from calcified and inflamed aortas of 12 patients with high serum levels of MMP-9 protein. AAA-MSCs expressed typical mesenchymal markers and, in line with the histological analysis, elevated levels of OPN, an osteogenic marker also involved in vascular remodelling. AAA-MSCs were highly osteogenic and underwent intense calcium deposition under proper stimulation; moreover, AAA-MSCs were able to differentiate into tubule-like structures in Matrigel, even if the lack of CD146 and the reduced structural stability suggested an inefficient maturation process. We further demonstrated an association between osteogenesis and inflammation; indeed, ha-MSCs cultured with either cytokines (TNF-α, IL-1β) or AAA-PBMCs showed increased expression of MMP-9 and osteogenic markers, to the detriment of the adipogenic regulator PPAR-γ. Interestingly, the culture with inflammatory cells highly stimulated ha-MSCs towards the osteogenic commitment.ConclusionsAAA-MSCs displayed high osteogenic potential and pathological angiogenesis that represent crucial steps for AAA progression; we showed that the inflammatory process critically addresses human vascular MSCs towards a pathological behaviour, inducing vascular bone matrix deposition and remodelling. Inhibition of this pathway may represent a pharmacological approach against arterial calcification.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0554-x) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The crosstalk between vascular MSCs and inflammatory mediators determines the pro-calcific remodelling of human atherosclerotic aneurysm

et al. 2017

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“…The alterations of elastin and collagen are the consequence of proteases production by arterial wall cells, such as smooth muscle cells of the tunica media, adventitia fibroblasts and cells constituting inflammatory infiltrates. Proteases and in particular metallo-proteases (MMP), are closely linked with aneurysm (Ciavarella et al, 2015;Longo et al, 2002;Tromp et al, 2004).…”

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confidence: 99%

Abdominal aortic aneurysm and histological, clinical, radiological correlation

et al. 2016

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“…Lastly, while prior clinical studies have shown a positive effect of statin therapy in ruptured intracranial aneurysms and abdominal aortic aneurysms treated with endovascular methods, the biology of these aneurysms differs substantially from that of unruptured intracranial aneurysms. For example, prior studies have shown that stable unruptured aneurysms do not exhibit increased expression of MMPs, while ruptured intracranial aneurysms and abdominal aortic aneurysms do 23 24. In addition, unruptured aneurysms have significantly lower expression of a number of markers of inflammation than ruptured aneurysms 25.…”

Section: Discussionmentioning

confidence: 99%

Statins are not associated with short-term improved aneurysm healing in a rabbit model of unruptured aneurysms

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Dai

et al. 2016

J NeuroIntervent Surg

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Human Vascular Wall Mesenchymal Stromal Cells Contribute to Abdominal Aortic Aneurysm Pathogenesis Through an Impaired Immunomodulatory Activity and Increased Levels of Matrix Metalloproteinase-9

Cited by 27 publications

References 29 publications

The crosstalk between vascular MSCs and inflammatory mediators determines the pro-calcific remodelling of human atherosclerotic aneurysm

The crosstalk between vascular MSCs and inflammatory mediators determines the pro-calcific remodelling of human atherosclerotic aneurysm

Abdominal aortic aneurysm and histological, clinical, radiological correlation

Statins are not associated with short-term improved aneurysm healing in a rabbit model of unruptured aneurysms

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