Abstract
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-1α (HIF-1α) on the migration of BM-MSCs and to analyze the interaction between HIF-1α and integrin-mediated signals. Hypoxia-activated HIF-1α significantly increased BM-MSC migration. The expression of integrin α 4 was decreased in BM-MSCs by increased HIF-1α under hypoxia, whereas the expression of Rho-associated kinase 1 (ROCK1) and Rac1/2/3 was increased. After downregulation of HIF-1α by YC-1, which is an inhibitor of HIF-1α, BM-MSC migration was decreased via upregulation of integrin α 4 and downregulation of ROCK1 and Rac1/2/3. Knockdown of integrin α 4 by integrin α 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-1α expression and augmented the translocation of HIF-1α into the nucleus under hypoxia. Taken together, the alternative expression of HIF-1α induced by microenvironment factors, such as hypoxia and integrin α 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.
Highlights
Mesenchymal stem cells (MSCs) are adult multipotent stem cells capable of differentiation into cells originating from any of the three germ layers, that is, the endoderm, mesoderm, and ectoderm [1]
To confirm the effect of hypoxia on the migration of bone marrow-derived mesenchymal stem cells (BM-MSCs), we analyzed the expression of hypoxia-inducible factor-1α (HIF-1α)
While the migration of BM-MSCs was significantly augmented under hypoxic conditions compared with normoxic conditions, the migration was suppressed by YC-1 pretreatment under both normoxic and hypoxic conditions (P < 0.05; Figure 1(e))
Summary
Mesenchymal stem cells (MSCs) are adult multipotent stem cells capable of differentiation into cells originating from any of the three germ layers, that is, the endoderm, mesoderm, and ectoderm [1]. To maximize the therapeutic efficacy of stem cell therapy using BM-MSCs, several requisite characteristics should be established: (1) a high survival rate and a high proliferative potential of transplanted cells; (2) effective homing properties; and (3) sufficient interactions between grafted MSCs and environmental factors at sites where MSCs have migrated [8]. Among these factors, effective homing, which is the capability of MSCs to migrate into target sites, is the most important and challenging characteristic to achieve [9]. Kim et al reported that pretreatment with tumor necrosis factor-α, a cytokine involved in acute inflammation, enhanced the adhesiveness
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