Abstract
BackgroundThe ability of mesenchymal stem cells (MSCs) to migrate to the desired tissues or lesions is crucial for stem cell-based regenerative medicine and tissue engineering. Optimal therapeutics for promoting MSC migration are expected to become an effective means for tissue regeneration. Electromagnetic fields (EMF), as a noninvasive therapy, can cause a lot of biological changes in MSCs. However, whether EMF can promote MSC migration has not yet been reported.MethodsWe evaluated the effects of EMF on cell migration in human bone marrow-derived MSCs. With the use of Helmholtz coils and an EMF stimulator, 7.5, 15, 30, 50, and 70 Hz/1 mT EMF was generated. Additionally, we employed the l-type calcium channel blocker verapamil and the focal adhesion kinase (FAK) inhibitor PF-573228 to investigate the role of intracellular calcium content, cell adhesion proteins, and the Rho GTPase protein family (RhoA, Rac1, and Cdc42) in EMF-mediated MSC migration. Cell adhesion proteins (FAK, talin, and vinculin) were detected by Western blot analysis. The Rho GTPase protein family activities were assessed by G-LISA, and F-actin levels, which reflect actin cytoskeletal organization, were detected using immunofluorescence.ResultsAll the 7.5, 15, 30, 50, and 70 Hz/1 mT EMF promoted MSC migration. EMF increased MSC migration in an intracellular calcium-dependent manner. Notably, EMF-enhanced migration was mediated by FAK activation, which was critical for the formation of focal contacts, as evidenced by increased talin and vinculin expression. Moreover, RhoA, Rac1, and Cdc42 were activated by FAK to increase cytoskeletal organization, thus promoting cell contraction.ConclusionsEMF promoted MSC migration by increasing intracellular calcium and activating the FAK/Rho GTPase signaling pathways. This study provides insights into the mechanisms of MSC migration and will enable the rational design of targeted therapies to improve MSC engraftment.
Highlights
The ability of mesenchymal stem cells (MSCs) to migrate to the desired tissues or lesions is crucial for stem cell-based regenerative medicine and tissue engineering
Adhesive cells often migrate in the so-called mesenchymal mode, in which the migrating cell undergoes rear-to-front polarization, protrusion and adhesion formation, and rear retraction. All these major steps in cell migration are orchestrated by numerous scaffold, adaptor, and adhesion proteins in concerted actions that are regulated by various signaling molecules, including protein kinase C (PKC), mitogen-activated protein kinases (MAPK; c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38), Rho GTPase, Rho kinase, and focal adhesion kinase (FAK) [10,11,12,13]
The results showed that Electromagnetic fields (EMF) at all selected frequencies (7.5, 15, 30, 50, and 75 Hz) promoted MSC migration to varying degrees (Fig. 2)
Summary
The ability of mesenchymal stem cells (MSCs) to migrate to the desired tissues or lesions is crucial for stem cell-based regenerative medicine and tissue engineering. MSCs can be isolated from several adult tissues, readily expanded in vitro, and exhibit robust immunomodulatory properties. All these highly desirable attributes make MSCs a stem cell source for the development of regenerative medicines. The migrating or homing ability of stem cells to the desired tissues or lesions is crucial for normal tissue morphogenesis, homeostasis, and repair, and for development of stem cell-based regenerative medicines [7,8,9]. All these major steps in cell migration are orchestrated by numerous scaffold, adaptor, and adhesion proteins (e.g., actin, myosin, integrin, paxillin, and tensin) in concerted actions that are regulated by various signaling molecules, including protein kinase C (PKC), mitogen-activated protein kinases (MAPK; c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38), Rho GTPase, Rho kinase, and focal adhesion kinase (FAK) [10,11,12,13]
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