Medicine Research Center, Weifang Medical College, Weifang, Shandong, People's Republic of China.
PLoS One. 2012;7(11):e50899. doi: 10.1371/journal.pone.0050899. Epub 2012 Nov 30.
Bone marrow-derived endothelial progenitor cells (EPCs), especially late EPCs, play a critical role in endothelial maintenance and repair, and postnatal vasculogenesis. Although the actin cytoskeleton has been considered as a modulator that controls the function and modulation of stem cells, its role in the function of EPCs, and in particular late EPCs, remains poorly understood.
METHODOLOGY/PRINCIPAL FINDING: Bone marrow-derived late EPCs were treated with jasplakinolide, a compound that stabilizes actin filaments. Cell apoptosis, proliferation, adhesion, migration, tube formation, nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation were subsequently assayed in vitro. Moreover, EPCs were locally infused into freshly balloon-injured carotid arteries, and the reendothelialization capacity was evaluated after 14 days. Jasplakinolide affected the actin distribution of late EPCs in a concentration and time dependent manner, and a moderate concentration of (100 nmol/l) jasplakinolide directly stabilized the actin filament of late EPCs. Actin stabilization by jasplakinolide enhanced the late EPC apoptosis induced by VEGF deprivation, and significantly impaired late EPC proliferation, adhesion, migration and tube formation. Furthermore, jasplakinolide attenuated the reendothelialization capacity of transplanted EPCs in the injured arterial segment in vivo. However, eNOS phosphorylation and NO production were increased in late EPCs treated with jasplakinolide. NO donor sodium nitroprusside (SNP) rescued the functional activities of jasplakinolide-stressed late EPCs while the endothelial NO synthase inhibitor L-NAME led to a further dysfunction induced by jasplakinolide in late EPCs.
CONCLUSIONS/SIGNIFICANCE: A moderate concentration of jasplakinolide results in an accumulation of actin filaments, enhancing the apoptosis induced by cytokine deprivation, and impairing the proliferation and function of late EPCs both in vitro and in vivo. NO donor reverses these impairments, suggesting the role of NO-related mechanisms in jasplakinolide-induced EPC downregulation. Actin cytoskeleton may thus play a pivotal role in regulating late EPC function.
骨髓来源的内皮祖细胞（EPCs），尤其是晚期 EPCs，在维持和修复内皮以及出生后的血管生成中起着关键作用。虽然肌动蛋白细胞骨架被认为是调节干细胞功能和调节的调节剂，但它在 EPCs 功能中的作用，特别是晚期 EPCs 的功能，仍然知之甚少。
方法/主要发现：用 jasplakinolide（一种稳定肌动蛋白丝的化合物）处理骨髓来源的晚期 EPCs。随后在体外检测细胞凋亡、增殖、黏附、迁移、管形成、一氧化氮（NO）产生和内皮型一氧化氮合酶（eNOS）磷酸化。此外，将 EPCs 局部注入新鲜球囊损伤的颈动脉，并在 14 天后评估再内皮化能力。jasplakinolide 以浓度和时间依赖的方式影响晚期 EPC 的肌动蛋白分布，适中浓度（100nmol/l）jasplakinolide 直接稳定晚期 EPC 的肌动蛋白丝。jasplakinolide 稳定肌动蛋白增强了 VEGF 剥夺诱导的晚期 EPC 凋亡，并显著损害晚期 EPC 的增殖、黏附、迁移和管形成。此外，jasplakinolide 减弱了移植 EPC 在体内损伤动脉段的再内皮化能力。然而，用 jasplakinolide 处理的晚期 EPCs 中 eNOS 磷酸化和 NO 产生增加。NO 供体硝普钠（SNP）挽救了 jasplakinolide 应激晚期 EPC 的功能活性，而内皮型一氧化氮合酶抑制剂 L-NAME 导致 jasplakinolide 在晚期 EPC 中进一步功能障碍。
结论/意义：适中浓度的 jasplakinolide 导致肌动蛋白丝积累，增强细胞因子剥夺诱导的凋亡，并损害体外和体内晚期 EPC 的增殖和功能。NO 供体逆转了这些损伤，表明 NO 相关机制在 jasplakinolide 诱导的 EPC 下调中起作用。因此，肌动蛋白细胞骨架可能在调节晚期 EPC 功能方面发挥关键作用。
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