Cancer Research Institute, Department of Medical Lifescience, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
Cancer Research Institute, Department of Medical Lifescience, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
Biochem Biophys Res Commun. 2018 Jul 2;501(4):941-947. doi: 10.1016/j.bbrc.2018.05.086. Epub 2018 May 24.
Mesenchymal stromal/stem cells (MSCs) have been promising source for regenerative cell therapy in ischemic diseases. To improve efficacy of MSC therapy, various priming methods have been developed, and hypoxic priming has been reported to enhance therapeutic efficacy of MSCs by increasing secretion level of growth factors and cytokines. Recently, it has been reported that bone marrow MSCs primed with hypoxic condition show an increase of autophagy. Here, we addressed whether proangiogenic activity increased by hypoxic condition is associated with autophagy. Wharton's jelly derived MSCs primed with hypoxia showed increase of autophagy with increased hypoxia inducible factor-1α level, and conditioned medium (CM) derived from these cells showed increased levels of migration and tube formation of human umbilical vein endothelial cells (HUVECs) compared to non-primed MSCs-derived CM. Pretreatment with autophagy inhibitor 3-methyladenine or chloroquine prior to exposure of hypoxia resulted in reduction of migration and tube formation of HUVECs. CM obtained under hypoxic condition from MSCs in which autophagy activity was inhibited by ATG5 and ATG7 siRNA treatment also showed decrease of migration and tube formation of HUVECs. Accordingly, secretion levels of angiogenin and VEGF that were markedly increased upon hypoxia exposure was decreased by ATG5/7 knockdown. Therefore, it may be suggested that autophagy plays an important role in hypoxia-driven enhancement of paracrine effect of MSCs.
间充质基质/干细胞（MSCs）一直是缺血性疾病再生细胞治疗有希望的来源。为了提高 MSC 治疗的疗效，已经开发了各种启动方法，并且已经报道低氧预培养通过增加生长因子和细胞因子的分泌水平来增强 MSCs 的治疗效果。最近，据报道，骨髓 MSC 在低氧条件下预培养会增加自噬。在这里，我们研究了低氧条件下增加的促血管生成活性是否与自噬有关。用低氧预培养的 Wharton 胶衍生 MSC 显示自噬增加，缺氧诱导因子-1α水平升高，与非预培养 MSC 衍生的 CM 相比，这些细胞的条件培养基 (CM) 显示人脐静脉内皮细胞 (HUVEC) 的迁移和管形成增加。在用低氧预处理之前，用自噬抑制剂 3-甲基腺嘌呤或氯喹预处理会导致 HUVEC 的迁移和管形成减少。在用 ATG5 和 ATG7 siRNA 处理抑制 MSC 中自噬活性的情况下，从低氧条件下获得的 CM 也显示 HUVEC 的迁移和管形成减少。因此，在缺氧暴露时显著增加的血管生成素和 VEGF 的分泌水平通过 ATG5/7 敲低降低。因此，可以认为自噬在低氧驱动的 MSC 旁分泌作用增强中起重要作用。
