Autophagy mediates enhancement of proangiogenic activity by hypoxia in mesenchymal stromal/stem cells

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.