Epidermal growth factor as candidate for ex vivo expansion of bone marrow-derived mesenchymal stem cells

¹ University of Pittsburgh, Pittsburgh, Pennsylvania
² Massachusetts Institute of Technology, Boston, Massachusetts

^* To whom correspondence should be addressed. E-mail: wellsa{at}upmc.edu.

	Abstract

Bone marrow mesenchymal stem cells (BMMSC) are pluripotent cells capable of differentiating into several cell types and are thus an attractive cell source for connective tissue engineering. A challenge in such utilization is expansion and directed seeding in vitro, requiring proliferation and survival, and directed migration respectively, prior to functional differentiation. The epidermal growth factor receptor (EGFR) is the prototypal growth factor receptor and elicits these responses from a wide variety of stromal cells, epithelial, and endothelial cells. Ligands for this receptor are appealing for use in tissue engineering because they are relatively resistant to biological extremes and amenable to high volume production. Therefore, we determined whether an EGFR ligand, EGF, could be utilized for ex vivo expansion of BMMSC. EGF stimulated motility in rat and immortalized human BMMSC. EGF-induced proliferation was observed in immortalized human BMMSC, but was not apparent in rat BMMSC under our experimental conditions. EGF did not, however, rescue either BMMSC from apoptosis due to lack of serum. Examining key signaling intermediaries, EGF caused robust phosphorylation of ERK and AKT but only minimal phosphorylation of EGFR and PLC in rat BMMSC, while these intermediaries were all strongly activated in the human BMMSC. EGF also induced robust ERK activation in primary porcine MSC. EGF pretreatment or co-treatment did not interfere with secondarily induced differentiation of either of the BMMSC into adipogenic or osteogenic lineages. PDGF effects were similar to, and not additive with, those elicited by EGF, with some quantitative differences; however, PDGF did interfere with the differentiation of these BMMSC. These findings suggest that EGFR ligands could be utilized for ex vivo expansion and direction of BMMSC.

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