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

Autor: Adil Rasheed, Katey J. Rayner, Benjamin Hibbert, Trevor Simard, Sarah A. Shawky, Ricky Tsai, Richard G. Jung, Carolyn L. Cummins, Michael F. Saikali
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Agonist
Benzylamines
Endothelium
endocrine system diseases
medicine.drug_class
Population
early outgrowth cells
Benzoates
03 medical and health sciences
Mice
0302 clinical medicine
Tissue‐specific Progenitor and Stem Cells
medicine
Animals
Humans
Progenitor cell
lcsh:QH573-671
Liver X receptor
education
Endothelial Progenitor Cells
Liver X Receptors
Secretome
Mice
Knockout
autologous cell therapy
education.field_of_study
lcsh:R5-920
Chemistry
lcsh:Cytology
Monocyte
Cell Biology
General Medicine
female genital diseases and pregnancy complications
030104 developmental biology
medicine.anatomical_structure
secreted factors
Culture Media
Conditioned
Cancer research
Bone marrow
atherosclerosis
lcsh:Medicine (General)
030217 neurology & neurosurgery
Ex vivo
Developmental Biology
liver X receptor
Zdroj: Stem Cells Translational Medicine, Vol 10, Iss 3, Pp 479-491 (2021)
Stem Cells Translational Medicine
ISSN: 2157-6564
2157-6580
Popis: 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 (Lxrαβ−/−) 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 Lxrαβ−/− 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.
Bone marrow cells differentiated with liver x receptors agonist (GW) produce a population of early outgrowth cells (EOCs) with an alternative secretome, capable of decreasing monocyte‐endothelial adhesion in culture, and reducing atherosclerosis in vivo. GW‐treated EOCs derived from peripheral blood mononuclear cells (MNCs) of patients with coronary artery disease also produced a secretome that reduced monocyte‐endothelial adhesion in culture.
Databáze: OpenAIRE
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