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The Journal of Neuroscience, May 31, 2006, 26(22):5996-6003; doi:10.1523/JNEUROSCI.5380-05.2006
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Development/Plasticity/Repair
Matrix Metalloproteinase 2 (MMP2) and MMP9 Secreted by Erythropoietin-Activated Endothelial Cells Promote Neural Progenitor Cell Migration
Lei Wang,1 Zheng Gang Zhang,1 Rui Lan Zhang,1 Sara R. Gregg,1 Ann Hozeska-Solgot,1 Yvonne LeTourneau,1 Ying Wang,1 andMichael Chopp1,2 1Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, and 2Department of Physics, Oakland University, Rochester, Michigan 48309
Correspondence should be addressed to Dr. Zheng Gang Zhang, Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202. Email: zhazh{at}neuro.hfh.edu
We investigated the hypothesis that endothelial cells activated by erythropoietin (EPO) promote the migration of neuroblasts. This hypothesis is based on observations in vivo that treatment of focal cerebral ischemia with EPO enhances the migration of neuroblasts to the ischemic boundary, a site containing activated endothelial cells and angiogenic microvasculature. To model the microenvironment within the ischemic boundary zone, we used a coculture system of mouse brain endothelial cells (MBECs) and neural progenitor cells derived from the subventricular zone of the adult mouse. Treatment of MBECs with recombinant human EPO (rhEPO) significantly increased secretion of matrix metalloproteinase 2 (MMP2) and MMP9. rhEPO-treated MBEC supernatant as conditioned medium significantly increased the migration of neural progenitor cells. Application of an MMP inhibitor abolished the supernatant-enhanced migration. Incubation of neurospheres alone with rhEPO failed to increase progenitor cell migration. rhEPO activated phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase (ERK1/2) in MBECs. Selective inhibition of the PI3K/Akt and ERK1/2 pathways significantly attenuated the rhEPO-induced MMP2 and MMP9, which suppressed neural progenitor cell migration promoted by the rhEPO-activated MBECs. Collectively, our data show that rhEPO-activated endothelial cells enhance neural progenitor cell migration by secreting MMP2 and MMP9 via the PI3K/Akt and ERK1/2 signaling pathways. These data demonstrate that activated endothelial cells can promote neural progenitor cell migration, and provide insight into the molecular mechanisms underlying the attraction of newly generated neurons to injured areas in brain.
Key words: rhEPO; migration; MMP2; MMP9; neural progenitor cell; mouse brain endothelial cell
Received Dec. 16, 2005; revised April 25, 2006; accepted April 26, 2006.
Correspondence should be addressed to Dr. Zheng Gang Zhang, Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202. Email: zhazh{at}neuro.hfh.edu
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