Open AccessLoss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells
Author(s) -
Rasheed Adil,
Tsai Ricky,
Cummins Carolyn L.
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.007787
Subject(s) - progenitor cell , haematopoiesis , liver x receptor , myeloid , stem cell , endothelial stem cell , medicine , endocrinology , cholesterol , monocyte , ldl receptor , bone marrow , endothelial progenitor cell , biology , hematopoietic stem cell , immunology , microbiology and biotechnology , cancer research , lipoprotein , nuclear receptor , biochemistry , in vitro , gene , transcription factor
Background The liver X receptors ( LXRs ; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of LXR s and a high‐fat high‐cholesterol diet on global hematopoiesis, with special emphasis on endothelial progenitor cells ( EPC s), a vasoreparative cell type that is derived from bone marrow hematopoietic stem cells. Methods and Results Wild‐type and LXR double‐knockout ( Lxr αβ −/− ) mice were fed a Western diet ( WD ) to increase plasma cholesterol levels. In WD ‐fed Lxr αβ −/− mice, flow cytometry and complete blood cell counts revealed that hematopoietic stem cells, a myeloid progenitor, and mature circulating myeloid cells were increased; EPC numbers were significantly decreased. Hematopoietic stem cells from WD ‐fed Lxr αβ −/− mice showed increased cholesterol content, along with increased myeloid colony formation compared with chow‐fed mice. In contrast, EPC s from WD ‐fed Lxr αβ −/− mice also demonstrated increased cellular cholesterol content that was associated with greater expression of the endothelial lineage markers Cd144 and Vegfr2 , suggesting accelerated differentiation of the EPC s. Treatment of human umbilical vein endothelial cells with conditioned medium collected from these EPC s increased THP ‐1 monocyte adhesion. Increased monocyte adhesion to conditioned medium–treated endothelial cells was recapitulated with conditioned medium from Lxr αβ −/− EPC s treated with cholesterol ex vivo, suggesting cholesterol is the main component of the WD inducing EPC dysfunction. Conclusions LXR s are crucial for maintaining the balance of hematopoietic cells in a hypercholesterolemic environment and for mitigating the negative effects of cholesterol on EPC differentiation/secretome changes that promote monocyte‐endothelial adhesion.