Hypoxia-Inducible Factor-1α Is Essential for Hypoxia-Induced Mesenchymal Stem Cell Mobilization into the Peripheral Blood

Mobilization of mesenchymal stem cells (MSCs) is a promising strategy for tissue repair and regenerative medicine. The establishment of an appropriate animal model and clarification of the underlying mechanisms are beneficial to develop the mobilization regimens for therapeutic use. In this study, we therefore established a rat MSC mobilization model and investigated the related mechanisms, using continuous hypoxia as the mobilizing stimulus. We found that MSCs could be mobilized into peripheral blood of rats exposed to short-term hypoxia (2 days) and the mobilization efficiency increased in a time-dependent manner (2-14 days). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) was upregulated during hypoxic exposure and was expressed continuously in bone marrow. Inhibition of HIF-1 alpha expression by YC-1 remarkably reduced the number of mobilized MSCs, suggesting that HIF-1 alpha is essential for hypoxia-induced MSC mobilization. Further, we investigated the potential role of HIF-1 alpha target genes, vascular endothelial growth factor (VEGF), and stromal cell-derived factor-1 alpha (SDF-1 alpha). VEGF expression was elevated from day 2 to day 7 of hypoxia, stimulating an increase in bone marrow sinusoidal vessels and possibly facilitating the egress of MSCs. SDF-1 alpha protein levels were increased in the peripheral blood of rats during MSC mobilization and promoted the migration of MSCs under hypoxic conditions in vitro. These results suggest that HIF-1 alpha plays a pivotal role in hypoxia-induced MSC mobilization, possibly acting via its downstream genes VEGF and SDF-1 alpha. These data provide a novel insight into the mechanisms responsible for MSC mobilization and may help in the development of clinically useful therapeutic agents.