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Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis.

ABSTRACT: Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.

SUBMITTER: Li F

PROVIDER: S-EPMC5438961 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis.

Li Feifei F Guo Xia X Chen Shi-You SY

Frontiers in cardiovascular medicine 20170522

Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of athero ...[more]

PMID: 28589127

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Project description:UnlabelledMesenchymal stem cells (MSCs) exhibit immunosuppressive efficacy and significantly inhibit the formation of the atherosclerosis (AS) plaque in apolipoprotein E-knockout (apoE(-/-)) mice. Of note, the largest lymphoid organ, the skin, provides a readily accessible and ideal source of tissue for the isolation of MSCs: skin-derived MSCs (S-MSCs). However, the effect and the mechanism of the therapeutic properties of S-MSCs in the progression of AS are unclear. We therefore investigated a direct effect of S-MSC treatment in the formation of atherosclerotic plaque in apoE(-/-) mice. Fifty apoE(-/-) mice were divided into four groups: the control group (AS), the S-MSC treatment group (S-MSC treatment), the nuclear factor-κB (NF-κB)(-/-)-S-MSC treatment group (KO-S-MSC treatment), and the additional S-MSC migration group. Brachiocephalic artery ultrasound biomicroscope (UBM) analysis showed that S-MSC treatment significantly reduced lesion size compared with the control groups (p < .01). Histological studies demonstrated that the plaque area of the mouse aortic arch was significantly decreased after S-MSC treatment. All alterations were dependent on NF-κB activation. After tail-vein injection, S-MSCs were capable of migrating to atherosclerotic plaque and selectively taking up residence near macrophages. S-MSC treatment reduced the release of the proinflammatory cytokine tumor necrosis factor (TNF)-α and increased the expression of the anti-inflammatory factor interleukin (IL)-10 in the atherosclerotic plaque, which was also dependent on NF-κB activation. In vitro, we found lipopolysaccharide (LPS) induced NF-κB-dependent expression of cyclooxygenase-2 (COX-2) in S-MSCs. Prostaglandin E2 (PGE2) expression was markedly increased after LPS-stimulated S-MSCs were cocultured with macrophages. LPS-stimulated macrophages produced less TNF-α/IL-1β and more IL-10 when cultured with S-MSCs, and although both were dependent upon NF-κB, the release of IL-10 was diminished if the S-MSCs were pretreated with a COX-2 inhibitor or an EP2/EP4 antagonist. Our data demonstrated that S-MSCs inhibited the formation of the atherosclerotic plaque in apoE(-/-) mice by modulating the functionality of macrophages, suggesting that S-MSCs may potentially have a role in stem cell-based therapy for AS.SignificanceA combination of in vitro and in vivo experiments showed that skin-derived mesenchymal stem cells (S-MSCs) can attenuate the plaque size of atherosclerosis. This is probably because S-MSCs beneficially modulate the response of macrophages through an increased release of prostaglandin E2 acting on the EP2 and EP4 receptors of the macrophages, stimulating the production and release of the anti-inflammatory cytokine interleukin-10, and decreasing the production of proinflammatory cytokine tumor necrosis factor-α. S-MSCs inhibited the formation of the atherosclerotic plaque in apolipoprotein E-knockout mice by modulating the functionality of macrophages, and the suppressive property of S-MSCs is dependent on NF-κB signaling. This study provides direct evidence that S-MSCs have a potent immunosuppressive effect in the development of atherosclerosis in mice, suggesting that S-MSCs can easily be cultured and have similar function to bone marrow-derived MSCs, a promising cell source for stem cell-based therapies of atherosclerosis, and possibly also in transplantation.

Dataset Information

Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis.

Publications

Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis.

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