HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells.
Reendothelialization involves endothelial progenitor cell (EPC) homing, proliferation, and differentiation, which may be influenced by fluid shear stress and local flow pattern. This study aims to elucidate the role of laminar flow on embryonic stem (ES) cell differentiation and the underlying mechanism. We demonstrated that laminar flow enhanced ES cell-derived progenitor cell proliferation and differentiation into endothelial cells (ECs). Laminar flow stabilized and activated histone deacetylase 3 (HDAC3) through the Flk-1-PI3K-Akt pathway, which in turn deacetylated p53, leading to p21 activation. A similar signal pathway was detected in vascular endothelial growth factor-induced EC differentiation. HDAC3 and p21 were detected in blood vessels during embryogenesis. Local transfer of ES cell-derived EPC incorporated into injured femoral artery and reduced neointima formation in a mouse model. These data suggest that shear stress is a key regulator for stem cell differentiation into EC, especially in EPC differentiation, which can be used for vascular repair, and that the Flk-1-PI3K-Akt-HDAC3-p53-p21 pathway is crucial in such a process.
Zeng
Lingfang
L
Department of Cardiac and Vascular Sciences, St. George's, University of London, London SW17 0RE, England, UK.
Xiao
Qingzhong
Q
Margariti
Andriana
A
Zhang
Zhongyi
Z
Zampetaki
Anna
A
Patel
Seema
S
Capogrossi
Maurizio C
MC
Hu
Yanhua
Y
Xu
Qingbo
Q
D000107:Acetylation; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D000067696:Ataxin-1; D000067528:Ataxins; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D017353:Gene Deletion; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013314:Stress, Mechanical; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology*; D000099186:Histone Deacetylase 3
D001057:Apolipoproteins E; D000067696:Ataxin-1; D000067528:Ataxins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D000099186:Histone Deacetylase 3; C000593750:Atxn1 protein, mouse