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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0554-x) contains supplementary material, which is available to authorized users.

Pharmacological (or Synthetic) and Nutritional Agonists of PPAR-γ as Candidates for Cytokine Storm Modulation in COVID-19 Disease

“…Interestingly, PPAR-γ is expressed in macrophage-foam cells in human and murine atherosclerotic plaques [26,27], as well as in human and mouse monocyte and macrophages. In parallel, our research data showed that a low expression of PPAR-γ in mesenchymal stromal cells (MSCs) isolated from human abdominal aortic atherosclerotic plaques; moreover, we demonstrated that stimulation with inflammatory cytokines TNF-α/IL-1β reduced PPAR-γ expression in healthy vascular MSCs [28]. These findings support the inverse relationship between PPAR-γ and the inflammatory process and imply a regulatory ability of PPAR-γ on immune system and inflammatory circuits.…”

Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland

“…The vascular inflammation mobilizes the MSCs migration and adhesion in the gland or promotes the de novo MSCs proliferation due to the increased levels of pro-inflammatory cytokines, TGF-β or TNF-α. The crosstalk between vascular MSCs and inflammatory mediators, especially, interleukin-22, lead to MSCs proliferation, migration and osteogenic differentiation [ 266 , 267 ] under the influence of high levels of pineal melatonin and finally PGC formation. Brain tissue hypoxia : Many pathological conditions cause brain tissue hypoxia including hypertension, sleep apnea, stroke, and even respiratory disorders.…”

The Dual Nature of Mesenchymal Stem Cells (MSCs): Yin and Yang of the Inflammatory Process

“…AAA-MSCs were able to differentiate into endothelial-like cells, as demonstrated by the formation of a vascular network onto Matrigel and by the positivity to CD31 marker. Nevertheless, we observed a reduced expression of CD146, a pericyte marker, suggesting the instability and immaturity of the AAA-MSC-derived neo-vessels [37]. A representative image of AAA-MSC functional characteristics is reported in Figure 2.…”

“…An aberrant differentiation program of MSCs can be crucial in triggering the complications of the atherosclerotic plaque, like ectopic bone formation, and represents the early stage during calcification process [40]. AAA-MSCs also exhibited a marked osteogenic ability, correlating with the vascular calcium levels as measured by angio-CT in the enrolled patients [37]. Thus, it can be postulated that MSCs are key players during the renewal as well as the pathological conditions affecting the vascular wall.…”

“…The MSC behaviour can be seen as fine balance between two opposite forces, which is strongly influenced by the external microenvironment and the interaction with the neighboring cells. At this regard, the immune cells and the cytokines released during inflammation are key factors in exacerbating the osteogenic differentiation of healthy VW-MSCs [37].…”