Hypoxia Inducible Factor-1α Regulates the Migration of Bone Marrow Mesenchymal Stem Cells via Integrin α4

Although hypoxic environments have been known to regulate the migratory ability of bone marrow-derived mesenchymal stem cells (BM-MSCs), which is a critical factor for maximizing the therapeutic effect, the underlying mechanisms remain unclear. Therefore, we aimed to confirm the effect of hypoxia-inducible factor-1 alpha (HIF-1 alpha) on the migration of BM-MSCs and to analyze the interaction between HIF-1 alpha and integrin-mediated signals. Hypoxia-activated HIF-1 alpha significantly increased BM-MSC migration. The expression of integrin alpha(4) was decreased in BM-MSCs by increased HIF-1 alpha under hypoxia, whereas the expression of Rho-associated kinase 1 (ROCK1) and Rac1/2/3 was increased. After downregulation of HIF-1 alpha by YC-1, which is an inhibitor of HIF-1 alpha BM-MSC migration was decreased via upregulation of integrin alpha(4) and downregulation of ROCK1 and Rac1/2/3. Knockdown of integrin alpha(4) by integrin alpha(4) siRNA (siITGA4) treatment increased BM-MSC migration by upregulation of ROCK1, Rac1/2/3, and matrix metalloproteinase-2 regardless of oxygen tension. Moreover, siITGA4 treatment increased HIF-1 alpha expression and augmented the translocation of HIF-1 alpha into the nucleus under hypoxia. Taken together, the alternative expression of HIF-1 alpha induced by microenvironment factors, such as hypoxia and integrin alpha(4), may regulate the migration of BM-MSCs. These findings may provide insights to the underlying mechanisms of BM-MSC migration for successful stem cell-based therapy.