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.
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DOI：
10.1186/s13287-017-0554-x
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发表时间：
2017-04-26
影响因子：
7.5
通讯作者：
Pasquinelli G
中科院分区：
文献类型：
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作者：
Ciavarella C;Gallitto E;Ricci F;Buzzi M;Stella A;Pasquinelli G
人间充质干细胞（MSCs）具有众所周知的修复能力，但免疫调节活性和/或分化过程的任何缺陷都可能决定人类疾病的发展，包括影响血管壁的疾病。居住在人主动脉壁的间充质干细胞是动脉粥样硬化性动脉瘤发展的潜在细胞介质。用流式细胞仪对健康主动脉和动脉瘤主动脉分离的间充质干细胞进行鉴定，并检测其分化特性。然后对健康主动脉(ha)-MSCs进行炎症刺激，以评估微环境对其功能和参与血管重构的影响。从12例血清MMP-9蛋白高水平患者的钙化和炎症主动脉中分离出腹主动脉瘤(AAA)-MSCs。AAA-MSCs表达典型的间充质标志物，并且与组织学分析一致，OPN水平升高，OPN是一种也参与血管重塑的成骨标志物。AAA-MSCs具有高度成骨性，在适当的刺激下发生强烈的钙沉积；此外，在Matrigel中，AAA-MSCs能够分化成小管样结构，即使缺乏CD146和结构稳定性降低表明成熟过程效率低下。我们进一步证明了成骨和炎症之间的联系；事实上，用细胞因子（TNF-α, IL-1β）或aaa - pbmc培养的ha-MSCs显示MMP-9和成骨标志物的表达增加，损害脂肪生成调节剂PPAR-γ。有趣的是，炎症细胞培养高度刺激ha-MSCs向成骨承诺。AAA- mscs显示出高成骨潜能和病理性血管生成，这是AAA进展的关键步骤；我们发现炎症过程对人类血管间充质干细胞的病理行为至关重要，诱导血管骨基质沉积和重塑。抑制这一途径可能是一种对抗动脉钙化的药理学方法。本文的在线版本（doi:10.1186/s13287-017-0554-x）包含补充材料，可供授权用户使用。
Human 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. MSCs 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. Abdominal 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. AAA-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. The online version of this article (doi:10.1186/s13287-017-0554-x) contains supplementary material, which is available to authorized users.