Rho Inhibition Induces Migration of Mesenchymal Stromal Cells (MSCs)

¹ Institute of Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service, University of Frankfurt, Germany
² Chemotherapeutic Research Institute Georg Speyer Haus, Frankfurt, Germany

^* To whom correspondence should be addressed. E-mail: rhenschler{at}web.de.

	Abstract

Although Mesenchymal Stromal Cells (MSCs) are being increasingly used as cell therapeutics in clinical trials, the mechanisms which regulate their chemotactic migration behaviour are incompletely understood. We aimed to better define the ability of the GTPase regulator of cytoskeletal activation, Rho, to modulate migration induction in MSCs in a transwell chemotaxis assay. We found that culture-expanded MSCs migrate poorly towards exogenous phospholipids Lysophosphatidic acid (LPA) and Sphingosine-1-Phosphate (S1P) in transwell assays. Moreover, plasma-induced chemotactic migration of MSCs was even inhibited after pre-treatment with LPA. LPA treatment activated intracellular Rho and increased actin stress fibres in resident MSCs. Very similar cytoskeletal changes were observed after microinjection of a cDNA encoding constitutively active RhoA (RhoAV14) in MSCs. In contrast, microinjection of cDNA encoding Rho inhibitor C3 transferase led to resolution of actin stress fibres, appearance of a looser actin meshwork, and increased numbers of cytoplasmic extensions in the MSCs. Surprisingly, in LPA-pretreated MSCs migrating towards plasma, simultaneous addition of Rho inhibitor C2I-C3 reversed LPA-induced migration suppression and led to improved migration. Moreover, addition of Rho inhibitor C2I-C3 resulted in an approximately 3-10 fold enhancement of chemotactic migration towards LPA, S1P, as well as platelet-derived growth factor (PDGF) or hepatocyte growth factor (HGF). Thus, inhibition of Rho induces rearrangement of actin cytoskeleton in MSCs and renders them susceptible to induction of migration by physiological stimuli.

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