Platelet-Activating Factor Receptor Mediates Oxidized Low Density Lipoprotein-Induced Migration of Bone Marrow-Derived Mesenchymal Stem Cells

Abstract

Background: Oxidized low density lipoprotein (oxLDL) is involved in the development of vascular diseases. Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glyero-3-phosphorylcholine) is a key component of oxLDL. Methods: In the present study, we evaluate whether oxLDL can regulate migration of human bone-marrow derived stem cells (hBMSCs) and characterize the role of PAF in the oxLDL-induced migration. Results and Conclusions: oxLDL stimulated chemotaxis of hBMSCs in vitro. Treatment of the cells with BN52021, a specific antagonist of PAF receptor (PAF-R), completely blocked the cell migration induced by PAF, but not platelet-derived growth factor (PDGF-BB). Using PAF-R-specific small interfering RNA, it was demonstrated that silencing of endogenous PAF-R expression significantly attenuated cell migration induced by PAF, but not PDGF-BB, suggesting the specific involvement of PAF-R in the oxLDL-induced cell migration. In addition, PAF-induced migration of hBMSCs was abrogated by pretreating cells with mitogen-activated protein kinase (MAPK) inhibitors, including the MEK inhibitor U0126, the p38 MAPK inhibitor SB202190, and the JNK inhibitor SP600125. Moreover, adenoviral overexpression of a dominant negative mutant of p38 MAPK blocked PAF-stimulated migration. Taken together, these results suggest that PAF plays a pivotal role in the oxLDL-induced recruitment of hBMSCs through mechanisms involving PAF-R-dependent activation of MAPKs.

Krüppel-like factor 4 mediates lysophosphatidic acid-stimulated migration and proliferation of PC3M prostate cancer cells

“…32 Recent evidence has shown that KLF4 expression can be induced by several factors, including PDGF-BB, POVPC, platelet-activating factor and all-trans retinoic acid in vascular smooth muscle cells and human bone marrow-derived mesenchymal stem cells. 18, 19, 22, 33, 34 POVPC has been reported to induce migration and phenotypic switching of vascular smooth muscle cells through a KLF4-dependent mechanism. 17 In the current study, we demonstrated that LPA treatment resulted in increased expression of KLF4, and siRNA- or shRNA-mediated silencing of KLF4 showed abrogation of LPA-stimulated cell migration.…”

“…An increasing body of evidence suggests that KLF4 has a key role in chemotactic migration of several cell types, including mesenchymal stem cells, smooth muscle cells and cancer cells: 17, 18, 19 oxidized phospholipids have been reported to induce migration of vascular smooth muscle through a KLF4-dependent mechanism. 17 We have previously demonstrated that platelet-activating factor or an oxidized phosphatidylcholine POVPC (1-palmitoyl-2-oxovaleroyl- sn -glycero-3-phosphorylcholine) stimulated migration of human bone marrow-derived mesenchymal stem cells by inducing expression levels of KLF4.…”

“…17 We have previously demonstrated that platelet-activating factor or an oxidized phosphatidylcholine POVPC (1-palmitoyl-2-oxovaleroyl- sn -glycero-3-phosphorylcholine) stimulated migration of human bone marrow-derived mesenchymal stem cells by inducing expression levels of KLF4. 18, 19 On the contrary, overexpression of KLF4 resulted in suppressed migration of several cell types, including vascular smooth muscle cells, MDA-MB-231 breast cancer cells and RKO human colon cancer cells. 20, 21, 22 Therefore, the role of KLF4 in the regulation of migration of prostate cancer cells is still unclear.…”

Oxidized low density lipoprotein, stem cells, and atherosclerosis

“…MSCs co-cultured with mature endothelial cells (ECs) have the ability to undergo milieu-dependent differentiation toward ECs [27]. Migrated MSCs from bone marrow may play a key role in the development of atherogenesis in response to ox-LDL, which could induce MSCs derived smooth muscle like cells to differentiate into foam cells [28,29]. …”

“…It has been proved that PAF-R may introduce ox-LDL induced MSC migration [28]. Ox-LDL contains platelet activating factor (PAF) and PAF-like phospholipids [51].…”