Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by SDF-1-CXCR4 and HGF-c-met axes and involves matrix metalloproteinases

¹ Department of Medicine, University of Alberta, Alberta, Canada
² Canadian Blood Services Research & Development, Edmonton, Alberta, Canada
³ University of Louisville, Louisville, Kentucky
⁴ Department of Medicine, University of Alberta, Alberta, Canada; Canadian Blood Services Research & Development, Edmonton, Alberta, Canada

^* To whom correspondence should be addressed. E-mail: anna.janowska{at}bloodservices.ca.

	Abstract

Human mesenchymal stem cells (MSC) are increasingly being considered in cell-based therapeutic strategies for regeneration of various organs/tissues. However, the signals required for their homing and recruitment to injured sites are not yet fully understood. Because stromal-derived factor (SDF)-1 and hepatocyte growth factor (HGF) become upregulated during tissue/organ damage, in this study we examined whether these factors chemoattract ex vivo-expanded MSC derived from bone marrow (BM) and umbilical cord blood (CB). Specifically, we investigated the expression by MSC of CXCR4 and c-met, the cognate receptors of SDF-1 and HGF, and their functionality after early and late passages of MSC. We also determined whether MSC express matrix metalloproteinases (MMPs), including MT1-MMP, matrix-degrading enzymes that facilitate the trafficking of hematopoietic stem cells. We maintained expanded BM- or CB-derived MSC for up to 15-18 passages with monitoring of the expression of (i) various tissue markers (cardiac and skeletal muscle, neural, liver and endothelial cells), (ii) functional CXCR4 and c-met, and (iii) MMPs. We found that, for up to 15-18 passages, both BM- and CB-derived MSC (i) express mRNA for cardiac, muscle, neural and liver markers, as well as the endothelial marker VE-cadherin, (ii) express CXCR4 and c-met receptors and are strongly attracted by SDF-1 and HGF gradients, (iii) express MMP-2 and MT1-MMP transcripts and proteins, and (iv) are chemoinvasive across the reconstituted basement membrane Matrigel. These in vitro results suggest that the SDF-1-CXCR4 and HGF-c-met axes, along with MMPs, may be involved in recruitment of expanded MSC to damaged tissues.

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