1 Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
2 HKU Shenzhen Institute of Research and Innovation, Hong Kong, China.
J Dent Res. 2018 Feb;97(2):218-225. doi: 10.1177/0022034517733741. Epub 2017 Oct 3.
Low efficiency of deriving endothelial cells (ECs) from adult stem cells hampers their utilization in tissue engineering studies. The purpose of this study was to investigate whether suppression of transforming growth factor beta (TGF-β) signaling could enhance the differentiation efficiency of dental pulp-derived stem cells into ECs. We initially used vascular endothelial growth factor A (VEGF-A) to stimulate 2 dental pulp-derived stem cells (dental pulp stem cells and stem cells from human exfoliated deciduous teeth [SHED]) and compared their differentiation capacity into ECs. We further evaluated whether the vascular endothelial growth factor receptor I (VEGF-RI)-specific ligand placental growth factor-1 (PlGF-1) could mediate endothelial differentiation. Finally, we investigated whether the TGF-β signaling inhibitor SB-431542 could enhance the inductive effect of VEGF-A on endothelial differentiation, as well as the underlying mechanisms involved. ECs differentiated from dental pulp-derived stem cells exhibited the typical phenotypes of primary ECs, with SHED possessing a higher endothelial differentiation potential than dental pulp stem cells. VEGFR1-specific ligand-PLGF exerted a negligible effect on SHED-ECs differentiation. Compared with VEGF-A alone, the combination of VEGF-A and SB-431542 significantly enhanced the endothelial differentiation of SHED. The presence of SB-431542 inhibited the phosphorylation of Suppressor of Mothers Against Decapentaplegic 2/3 (SMAD2/3), allowing for VEGF-A-dependent phosphorylation and upregulation of VEGFR2. Our results indicate that the combination of VEGF-A and SB-431542 could enhance the differentiation of dental pulp-derived stem cells into endothelial cells, and this process is mediated through enhancement of VEGF-A-VEGFR2 signaling and concomitant inhibition of TGF-β-SMAD2/3 signaling.
从成体干细胞中获得内皮细胞（ECs）的效率低，限制了其在组织工程研究中的应用。本研究旨在探讨抑制转化生长因子β（TGF-β）信号是否能提高牙髓来源干细胞向 ECs 分化的效率。我们最初使用血管内皮生长因子 A（VEGF-A）刺激 2 种牙髓来源干细胞（牙髓干细胞和人乳牙脱落牙髓干细胞[SHED]），并比较它们向 ECs 分化的能力。我们进一步评估了血管内皮生长因子受体 I（VEGF-RI）特异性配体胎盘生长因子-1（PlGF-1）是否能介导内皮分化。最后，我们研究了 TGF-β信号抑制剂 SB-431542 是否能增强 VEGF-A 对内皮分化的诱导作用，以及涉及的潜在机制。从牙髓来源干细胞分化而来的 ECs 表现出原代 ECs 的典型表型，SHED 比牙髓干细胞具有更高的内皮分化潜能。VEGFR1 特异性配体-PlGF 对 SHED-ECs 分化的作用可以忽略不计。与 VEGF-A 单独作用相比，VEGF-A 和 SB-431542 的联合使用显著增强了 SHED 的内皮分化。SB-431542 的存在抑制了 Suppressor of Mothers Against Decapentaplegic 2/3（SMAD2/3）的磷酸化，使 VEGF-A 依赖的 VEGFR2 磷酸化和上调成为可能。我们的结果表明，VEGF-A 和 SB-431542 的联合使用可以增强牙髓来源干细胞向内皮细胞的分化，这一过程是通过增强 VEGF-A-VEGFR2 信号和同时抑制 TGF-β-SMAD2/3 信号来介导的。
