Zhang Zhaocheng, Nör Felipe, Oh Min, Cucco Carolina, Shi Songtao, Nör Jacques E
Department of Cariology, Restorative Sciences and Endodontics, Angiogenesis Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
Stem Cells. 2016 Jun;34(6):1576-87. doi: 10.1002/stem.2334. Epub 2016 Mar 11.
Vasculogenesis is the process of de novo blood vessel formation observed primarily during embryonic development. Emerging evidence suggest that postnatal mesenchymal stem cells are capable of recapitulating vasculogenesis when these cells are engaged in tissue regeneration. However, the mechanisms underlining the vasculogenic differentiation of mesenchymal stem cells remain unclear. Here, we used stem cells from human permanent teeth (dental pulp stem cells [DPSC]) or deciduous teeth (stem cells from human exfoliated deciduous teeth [SHED]) as models of postnatal primary human mesenchymal stem cells to understand mechanisms regulating their vasculogenic fate. GFP-tagged mesenchymal stem cells seeded in human tooth slice/scaffolds and transplanted into immunodeficient mice differentiate into human blood vessels that anastomize with the mouse vasculature. In vitro, vascular endothelial growth factor (VEGF) induced the vasculogenic differentiation of DPSC and SHED via potent activation of Wnt/β-catenin signaling. Further, activation of Wnt signaling is sufficient to induce the vasculogenic differentiation of postnatal mesenchymal stem cells, while Wnt inhibition blocked this process. Notably, β-catenin-silenced DPSC no longer differentiate into endothelial cells in vitro, and showed impaired vasculogenesis in vivo. Collectively, these data demonstrate that VEGF signaling through the canonical Wnt/β-catenin pathway defines the vasculogenic fate of postnatal mesenchymal stem cells. Stem Cells 2016;34:1576-1587.
血管生成是主要在胚胎发育过程中观察到的从头开始形成血管的过程。新出现的证据表明，出生后的间充质干细胞在参与组织再生时能够重现血管生成。然而，间充质干细胞血管生成分化的潜在机制仍不清楚。在这里，我们使用来自人类恒牙的干细胞（牙髓干细胞 [DPSC]）或乳牙的干细胞（人脱落乳牙干细胞 [SHED]）作为出生后原发性人类间充质干细胞的模型，以了解调节其血管生成命运的机制。接种在人牙切片/支架中并移植到免疫缺陷小鼠体内的绿色荧光蛋白标记的间充质干细胞分化为与小鼠脉管系统吻合的人类血管。在体外，血管内皮生长因子 (VEGF) 通过有效激活 Wnt/β-连环蛋白信号通路诱导 DPSC 和 SHED 的血管生成分化。此外，Wnt 信号的激活足以诱导出生后的间充质干细胞发生血管生成分化，而 Wnt 抑制则阻断了这一过程。值得注意的是，β-连环蛋白沉默的 DPSC 在体外不再分化为内皮细胞，并且在体内显示出血管生成受损。总体而言，这些数据表明，通过经典 Wnt/β-连环蛋白途径的 VEGF 信号决定了出生后的间充质干细胞的血管生成命运。《干细胞》2016 年；34:1576 - 1587。
