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Review
. 2013:2013:561098.
doi: 10.1155/2013/561098. Epub 2013 Dec 5.

Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis

Leah A Marquez-Curtis  1 , Anna Janowska-Wieczorek  2
Affiliations
Review

Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis

Leah A Marquez-Curtis et al. Biomed Res Int. 2013.

Abstract

Mesenchymal stromal cells (MSCs) are currently being investigated in numerous clinical trials of tissue repair and various immunological disorders based on their ability to secrete trophic factors and to modulate inflammatory responses. MSCs have been shown to migrate to sites of injury and inflammation in response to soluble mediators including the chemokine stromal cell-derived factor-(SDF-)1, but during in vitro culture expansion MSCs lose surface expression of key homing receptors particularly of the SDF-1 receptor, CXCR4. Here we review studies on enhancement of SDF-1-directed migration of MSCs with the premise that their improved recruitment could translate to therapeutic benefits. We describe our studies on approaches to increase the CXCR4 expression in in vitro-expanded cord blood-derived MSCs, namely, transfection, using the commercial liposomal reagent IBAfect, chemical treatment with the histone deacetylase inhibitor valproic acid, and exposure to recombinant complement component C1q. These methodologies will be presented in the context of other cell targeting and delivery strategies that exploit pathways involved in MSC migration. Taken together, these findings indicate that MSCs can be manipulated in vitro to enhance their in vivo recruitment and efficacy for tissue repair.

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Figures

Figure 1
Figure 1
Mechanisms of MSC transendothelial migration towards injured tissue. Mesenchymal stromal cells (MSCs) express the α 4 β 1 integrin very late antigen (VLA)-4, and endothelial cells express the corresponding ligand, vascular cell adhesion molecule (VCAM)-1. The onset of inflammation in injured tissue causes the release of cytokines which upregulate VCAM-1 and activates VLA-4, leading to initial arrest of MSC on the endothelium surface. MSCs also express a variety of homing receptors including CXCR4, CD44, CCR1, and c-Met, and their corresponding ligands, namely SDF-1, hyaluronic acid, M1P-1(alpha), and HGF, respectively, are upregulated at the site of tissue injury and/or hypoxia. These ligand-receptor interactions, as well as chemotactic bioactive lipids, modulate cell-cell contact between MSCs and endothelia cells. In addition, complement proteins that are stimulated by inflammation such as C1q, C3a, and C5a also chemoattract MSCs. Moreover, MSCs express the extracellular matrix-degrading enzymes, matrix metalloproteinase-(MMP-) 2 and membrane type (MT)1-MMP that play a role in their extravasation.
Figure 2
Figure 2
Approaches to enhance MSC migration by upregulating CXCR4. Cord blood-derived mesenchymal stromal cells (MSCs) were subjected to three treatments. (a) Transfection with CXCR4 plasmid using the liposomal reagent IBAfect led to a 105-fold increase in CXCR4 mRNA expression. (b) Priming MSCs with 5 mM valproic acid (VPA) increased trans-Matrigel chemoinvasion towards a low SDF-1 gradient (20 ng/mL) to a level comparable to that of untreated cells migrating towards a high SDF-1 gradient (100 ng/mL). (c) Exposure of MSCs to 10 μg/mL C1q also primed/enhanced trans-Matrigel migration towards SDF-1 and this was accompanied by over 6-fold increase in the surface expression of CXCR4 in C1q-treated cells.
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