Ox-LDL modifies the behaviour of bone marrow stem cells and impairs their endothelial differentiation via inhibition of Akt phosphorylation.
This study was to investigate the effect of oxidized low-density lipoprotein (ox-LDL) on the behaviour of bone marrow stem cells and their endothelial differentiation as well as the underlying mechanisms. Adult rat bone marrow multipotent progenitor cells (MAPCs) were incubated with ox-LDL for up to 2 weeks. Ox-LDL treatment resulted in a time- and dose-dependent reduction of MAPC population in culture through a combination of decreased cell proliferation and increased apoptosis. The expression of stem cell marker Oct-4 was significantly suppressed in MAPCs by ox-LDL in a dose- and time-dependant manner. Endothelial differentiation of MAPCs was substantially inhibited by ox-LDL with markedly decreased expression of endothelial markers vWF, Flk-1 and CD31, as well as impaired in vitro vascular structure formation. Ox-LDL-induced apoptosis and inhibition of Oct-4 expression, cell proliferation and endothelial differentiation of MAPCs were associated with significant inhibition of Akt phosphorylation. Akt overexpression in MAPCs transfected with a constitutively active Akt completely reversed the effects of ox-LDL on MAPCs including enhanced apoptosis, decreased cell proliferation, suppressed Oct-4 expression and endothelial differentiation as well as in vitro vascular structure formation. In conclusion, ox-LDL promotes apoptosis and inhibits Oct-4 expression and self-renewal of MAPCs, and impairs their endothelial differentiation via suppression of Akt signalling.
Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, Ohio State University Medical Center, Columbus, OH 43210, USA.
Ling
L
Chu
Hong
H
Hao
Min
M
Luo
Yu
Y
Huang
Zhenyu
Z
Chen
Tiewei
T
Lu
Xue
X
Zhao
Catherine M
CM
Verfaillie
Jay L
JL
Zweier
Zhenguo
Z
Liu
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000502:physiology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D014841:von Willebrand Factor / Q000096:biosynthesis
D008077:Lipoproteins, LDL; D050814:Octamer Transcription Factor-3; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D014841:von Willebrand Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt