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The secretome of liver X receptor agonist-treated early outgrowth cells decreases atherosclerosis in Ldlr-/- mice.

ABSTRACT: Endothelial progenitor cells (EPCs) promote the maintenance of the endothelium by secreting vasoreparative factors. A population of EPCs known as early outgrowth cells (EOCs) is being investigated as novel cell-based therapies for the treatment of cardiovascular disease. We previously demonstrated that the absence of liver X receptors (LXRs) is detrimental to the formation and function of EOCs under hypercholesterolemic conditions. Here, we investigate whether LXR activation in EOCs is beneficial for the treatment of atherosclerosis. EOCs were differentiated from the bone marrow of wild-type (WT) and LXR-knockout (Lxr??-/-) mice in the presence of vehicle or LXR agonist (GW3965). WT EOCs treated with GW3965 throughout differentiation showed reduced mRNA expression of endothelial lineage markers (Cd144, Vegfr2) compared with WT vehicle and Lxr??-/- EOCs. GW3965-treated EOCs produced secreted factors that reduced monocyte adhesion to activated endothelial cells in culture. When injected into atherosclerosis-prone Ldlr-/- mice, GW3965-treated EOCs, or their corresponding conditioned media (CM) were both able to reduce aortic sinus plaque burden compared with controls. Furthermore, when human EOCs (obtained from patients with established CAD) were treated with GW3965 and the CM applied to endothelial cells, monocyte adhesion was decreased, indicating that our results in mice could be translated to patients. Ex vivo LXR agonist treatment of EOCs therefore produces a secretome that decreases early atherosclerosis in Ldlr-/- mice, and additionally, CM from human EOCs significantly inhibits monocyte to endothelial adhesion. Thus, active factor(s) within the GW3965-treated EOC secretome may have the potential to be useful for the treatment of atherosclerosis.

SUBMITTER: Rasheed A

PROVIDER: S-EPMC7900590 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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The secretome of liver X receptor agonist-treated early outgrowth cells decreases atherosclerosis in Ldlr-/- mice.

Rasheed Adil A Shawky Sarah A SA Tsai Ricky R Jung Richard G RG Simard Trevor T Saikali Michael F MF Hibbert Benjamin B Rayner Katey J KJ Cummins Carolyn L CL

Stem cells translational medicine 20201124 3

Endothelial progenitor cells (EPCs) promote the maintenance of the endothelium by secreting vasoreparative factors. A population of EPCs known as early outgrowth cells (EOCs) is being investigated as novel cell-based therapies for the treatment of cardiovascular disease. We previously demonstrated that the absence of liver X receptors (LXRs) is detrimental to the formation and function of EOCs under hypercholesterolemic conditions. Here, we investigate whether LXR activation in EOCs is beneficia ...[more]

PMID: 33231376

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Project description:Background: Hepatic stellate cells (HSCs) are the primary collagen-secreting cells in the liver. While HSCs are the major cell type involved in the pathogenesis of liver fibrosis, hepatic macrophages also play an important role in mediating fibrogenesis and fibrosis resolution. Previously, we observed a reduction in HSC activation, proliferation, and collagen synthesis following exposure to human amnion epithelial cells (hAEC) and hAEC-conditioned media (hAEC-CM). This suggested that specific factors secreted by hAEC might be effective in ameliorating liver fibrosis. hAEC-derived extracellular vesicles (hAEC-EVs), which are nanosized (40-100 nm) membrane bound vesicles, may act as novel cell-cell communicators. Accordingly, we evaluated the efficacy of hAEC-EV in modulating liver fibrosis in a mouse model of chronic liver fibrosis and in human HSC. Methods: The hAEC-EVs were isolated and characterized. C57BL/6 mice with CCl4-induced liver fibrosis were administered hAEC-EV, hAEC-CM, or hAEC-EV depleted medium (hAEC-EVDM). LX2 cells, a human HSC line, and bone marrow-derived mouse macrophages were exposed to hAEC-EV, hAEC-CM, and hAEC-EVDM. Mass spectrometry was used to examine the proteome profile of each preparation. Results: The extent of liver fibrosis and number of activated HSCs were reduced significantly in CCl4-treated mice given hAEC-EVs, hAEC-CM, and hAEC EVDM compared to untreated controls. Hepatic macrophages were significantly decreased in all treatment groups, where a predominant M2 phenotype was observed. Human HSCs cultured with hAEC-EV and hAEC-CM displayed a significant reduction in collagen synthesis and hAEC-EV, hAEC-CM, and hAEC-EVDM altered macrophage polarization in bone marrow-derived mouse macrophages. Proteome analysis showed that 164 proteins were unique to hAEC-EV in comparison to hAEC-CM and hAEC-EVDM, and 51 proteins were co-identified components with the hAEC-EV fraction. Conclusion: This study provides novel data showing that hAEC-derived EVs significantly reduced liver fibrosis and macrophage infiltration to an extent similar to hAEC-EVDM and hAEC-CM. hAEC-EV-based therapy may be a potential therapeutic option for liver fibrosis.

Dataset Information

The secretome of liver X receptor agonist-treated early outgrowth cells decreases atherosclerosis in Ldlr-/- mice.

Publications

The secretome of liver X receptor agonist-treated early outgrowth cells decreases atherosclerosis in Ldlr-/- mice.

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