Abstract
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.
Highlights
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
We hypothesize that MSCs of vascular origin under inflammatory conditions may be addressed towards an aberrant pattern of differentiation and give rise to vascular lesions occurring during Abdominal aortic aneurysm (AAA) development, like calcium deposition, increased neo-vascularization and worsening of the inflammatory process
To further characterize the patient population, we evaluated the circulating levels of Matrix metalloproteinase-9 (MMP-9) protein, associated with vascular remodelling and inflammation
Summary
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. The mesenchymal stem cell (MSC) niche has been identified and characterized in several human adult tissues other than bone marrow [1,2,3]; as many researchers have reported, MSCs are endowed with self-renewal and, under the appropriate stimulation, are able to differentiate into multiple cell types along the mesodermal lineage (adipocytes, chondrocytes, osteocytes) [4] Thanks to these properties, MSCs regulate many reparative processes in the presence of tissue damage as well as keep the tissue homeostasis under physiologic conditions. Inflammation causes a reduced secretion of osteogenesis inhibitors and induces vascular smooth muscle cells (VSMCs) to secrete matrix vesicles where calcium precipitates, giving rise to calcification nodules [20] Based on these premises, we hypothesize that MSCs of vascular origin under inflammatory conditions may be addressed towards an aberrant pattern of differentiation and give rise to vascular lesions occurring during AAA development, like calcium deposition, increased neo-vascularization and worsening of the inflammatory process. We analysed the differentiation profile of AAA-MSCs; in order to explore the influence of inflammation on vascular MSCs, we exposed healthy aortic cells to inflammatory conditions and evaluated their differentiation tendencies
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