ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

Abstract

Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe -/-mice fed a chow or Western-type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1 -/-mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1-and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe -/-mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.

Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

“…HSC numbers were increased 1.5‐fold, accompanied by increases in myeloid progenitor populations (common myeloid progenitors, megakaryocyte‐erythrocyte progenitors, and GM progenitors), in the Lxr αβ −/− mice compared with their WT counterparts (Figure 1A). These changes are consistent with previous reports in which absence of the LXR target genes, Abca1 and Abcg1 or Apoe , allows for proliferation of the upstream HSCs and expansion of the myeloid progenitor cell populations 37, 38. There was no significant change in BM EPC numbers (Figure 1A), whereas in circulation, EPC numbers were reduced by 27% in the Lxr αβ −/− compared with WT mice (Figure 1B).…”

“…Although studies using knockout mice for the LXR target genes Abca1/g1 −/− or Apoe −/− have shown important roles for cholesterol in the development of monocytosis,37, 38 a role for LXRs per se in regulating global hematopoiesis, particularly within a hypercholesterolemic environment, has not been explored. Likewise, to our knowledge, quantitation of EPCs relative to other hematopoietic cell types has also not yet been investigated in any of these contexts.…”

“…Increased cholesterol content of HSCs has been previously demonstrated to increase their proliferation, leading to monocytosis 37, 38, 46. Herein, we have shown that WD feeding also increases the cholesterol content and proliferation of HSCs in Lxr αβ −/− mice (Figure 4C), not only pushing the fate of these HSCs towards the myeloid population but also away from the formation of EPCs (Figure 3A and 3B), suggesting that LXRs play a basal role in hematopoietic differentiation within the individual lineages.…”

“…One hypothesis, consistent with previous studies performed in mouse models absent LXR target genes, is that LXRs influence the subcellular distribution of cholesterol within EPCs. Indeed, Apoe −/− and Abca1/g1 −/− mice were shown to have an increase in cholesterol accumulation within lipid rafts of HSCs, leading to increased signaling through the common β subunit to enhance the production of myeloid cells 37, 38. In contrast, other studies demonstrated that LXR agonist treatment disrupted the localization of key signaling molecules vascular endothelial growth factor receptor 2 and protein kinase B within lipid rafts, suggesting that activation of LXRs decreases the intracellular distribution of cholesterol to the rafts 49, 50.…”

Human CD68 promoter GFP transgenic mice allow analysis of monocyte to macrophage differentiation in vivo

“…[4][5][6][7] Factors that enhance monocyte release from bone marrow into blood include chemokines derived from sites of inflammation, [8][9][10][11] and recent studies have identified hyperglycemia and hyperlipidemia as important factors that regulate monocytosis by acting on bone marrow progenitor cells. [12][13][14][15][16] Blood monocytes fall into 2 populations-Ly6C hi and Ly6C lo subsets that have been predicted to have different roles in vivo because of differential expression of chemokine receptors and different behaviors in intravital microscopy studies in which Ly6C lo monocytes have a vascular patrolling behavior.…”