Erythropoietin, a hypoxia-regulated factor, elicits a pro-angiogenic program in human mesenchymal stem cells

Zwezdaryk, K. J., Coffelt, S. B. , Figueroa, Y. G., Liu, J., Phinney, D. G., LaMarca, H. L., Florez, L., Morris, C. B., Hoyle, G. W. and Scandurro, A. B. (2007) Erythropoietin, a hypoxia-regulated factor, elicits a pro-angiogenic program in human mesenchymal stem cells. Experimental Hematology, 35(4), pp. 640-652. (doi: 10.1016/j.exphem.2007.01.044) (PMID:17379074)

Abstract

Objective: The ability of erythropoietin (EPO) to elicit a pro-angiogenic effect on human mesenchymal stem cells (hMSC) was tested. hMSC are currently under study as therapeutic delivery agents that target tumor vessels. Hypoxia favors the differentiation of hMSC towards a pro-angiogenic program. However, the classical angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, are not fully capable of restoring this effect. The hypoxia-regulated factor, EPO, induces angiogenesis in endothelial cells. Here, EPO's pro-angiogenic effect on hMSC was analyzed. Methods: hMSC were tested for EPO receptor expression by western blot, immunofluorescence, and flow cytometry assays. Downstream receptor signaling components JAK and STAT were measured by standard assays. Pro-angiogenesis effects mediated by EPO treatment of hMSC were measured by proliferation, cytokine, or pro-angiogenesis factor secretion, metalloprotease activation, migration, invasion, wound healing, and tubule formation assays. Results: hMSC express the cognate EPO receptor and are capable of promoting angiogenesis following EPO treatment in all the angiogenesis assays tested. EPO-treated hMSC proliferate and secrete pro-angiogenesis factors more readily than untreated hMSC. EPO leads to increased hMSC chemotaxis, migration, and activation of matrix metalloprotease-2. This treatment causes greater recruitment of vessels as measured in an in vivo angiogenesis assay. Conclusion: EPO is capable of eliciting a pro-angiogenesis program in hMSC that instigates secretion of angiogenic factors and the subsequent recruitment of endothelium. This study defines a novel mechanism for tumor cell recruitment of blood vessels that is important to consider in the design of stem cell–based therapies.

• Item Type: Articles
• Additional Information: This work was supported by the following grants: NIH AI056229, NIH 1P20RR20152-01, and a research grant award from Cancer Association of Greater New Orleans (CAGNO).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Coffelt, Professor Seth
• Authors: Zwezdaryk, K. J., Coffelt, S. B., Figueroa, Y. G., Liu, J., Phinney, D. G., LaMarca, H. L., Florez, L., Morris, C. B., Hoyle, G. W., and Scandurro, A. B.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Experimental Hematology
• Publisher: Elsevier
• ISSN: 0301472X
• Published Online: 28 March 2007