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TISSUE-SPECIFIC STEM CELLS |
a Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;
b Canadian Blood Services Research & Development, Edmonton, Alberta, Canada;
c University of Louisville, Louisville, Kentucky, USA
Key Words. Mesenchymal stem cells • Cord blood • Bone marrow • Matrix metalloproteinases • Membrane type 1-matrix metalloproteinase • Gene expression
Correspondence: Anna Janowska-Wieczorek, M.D., Ph.D., Department of Medicine, University of Alberta, CBS Building, 8249 114 St., Edmonton, AB T6G 2R8, Canada. Telephone: 780-431-8761; Fax: 780-702-8622; e-mail: anna.janowska{at}bloodservices.ca
Received June 15, 2005;
accepted for publication January 5, 2006.
Human mesenchymal stem cells (MSCs) 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 up-regulated during tissue/organ damage, in this study we examined whether these factors chemoattract ex vivo-expanded MSCs derived from bone marrow (BM) and umbilical cord blood (CB). Specifically, we investigated the expression by MSCs of CXCR4 and c-met, the cognate receptors of SDF-1 and HGF, and their functionality after early and late passages of MSCs. We also determined whether MSCs express matrix metalloproteinases (MMPs), including membrane type 1 (MT1)-MMP, matrix-degrading enzymes that facilitate the trafficking of hematopoietic stem cells. We maintained expanded BM- or CB-derived MSCs for up to 15–18 passages with monitoring of the expression of 1) various tissue markers (cardiac and skeletal muscle, neural, liver, and endothelial cells), 2) functional CXCR4 and c-met, and 3) MMPs. We found that for up to 15–18 passages, both BM- and CB-derived MSCs 1) express mRNA for cardiac, muscle, neural, and liver markers, as well as the vascular endothelial (VE) marker VE-cadherin; 2) express CXCR4 and c-met receptors and are strongly attracted by SDF-1 and HGF gradients; 3) express MMP-2 and MT1-MMP transcripts and proteins; and 4) are chemo-invasive 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 MSCs to damaged tissues.
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