HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells

Abstract

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.

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

“…Chen et al (22) demonstrated that LSS at 12 dynes/cm 2 strengthens the association of SIRT1 with eNOS to enhance NO production in ECs, which requires AMP-activated protein kinase phosphorylation of eNOS. Moreover, Zeng et al (23) demonstrated that LSS at 12 dynes/cm 2 modulates the differentiation of embryonic stem cellderived progenitor cells into ECs through the PI3K-Akt-HDAC3-p53 pathway. Zampetaki et al (8) recently demonstrated that Akt can associate with HDAC-3 to regulate EC survival in response to disturbed flow with OSS.…”

HDAC3: taking the SMRT-N-CoRrect road to repression

“…HDAC3 also deacetylates SRY, a master regulator of testis organogenesis, regulating its subcellular localization and activity (Thevenet et al, 2004). In addition, HDAC3-mediated deacetylation of p53 upon shear stress appears to be critical for differentiation of stem cells into epithelial cells (Zeng et al, 2006). Furthermore, HDAC3 deacetylates myocyte enhancer factor 2, a transcription factor important for differentiation, apoptosis and survival of different cell types (Gregoire et al, 2007), as well as glial cell missing (GCMa), which is important in development and differentiation (Chuang et al, 2006).…”

Mesenchymal Stem Cells: Roles and Relationships in Vascularization

“…29 Different flow patterns also have an effect on MSC differentiation. Laminar flow has shown increased VEGF production by MSCs but no change in cell morphology, 30 while dynamic rotational seeding resulted in vascular tube formation of MSCs. 31 The use of shear flow has also become especially popular in tissue-engineered vascular grafts.…”