Osteopontin is a mediator of the lateral migration of neuroblasts from the subventricular zone after focal cerebral ischemia.
We and others have shown that focal cerebral ischemia induces lateral migration of neuroblasts from the ipsilateral subventricular zone (SVZ) to the ischemic striatum. The signaling pathways underlying this phenomenon are not fully understood. The present study examined the role of osteopontin (OPN) in post-ischemic lateral migration of neuroblasts. Focal ischemia was induced by transient middle cerebral artery occlusion in adult spontaneous hypertensive rats. The expression of OPN in the ischemic brain was evaluated by immunohistochemistry, which showed that an up-regulation of OPN expression in the ipsilateral striatum at day 3, 7, 14 and 1 month of reperfusion with a peak at day 7. Double staining showed co-localization of OPN with ED1(+) macrophages/microglia in the ischemic regions. Inhibition of OPN activity by infusing a neutralizing antibody against OPN into the ischemic striatum significantly decreased the area covered with doublecortin(+) neuroblasts in the ipsilateral striatum. In vitro, OPN treatment did not affect the proliferation of neural progenitors, but induced an increased trans-well and radial migration of neural progenitors. The cultured neural progenitors expressed the OPN receptors CD44 and integrin beta(1). Blockade of the CD44 receptor had no effects on OPN mediated trans-well and radial migration of neural progenitors. However, blockade of integrin beta(1) receptor abolished the migration of neural progenitors in the absence or the presence of OPN. These results suggest that up-regulated expression of OPN produced by macrophages/microglia in the ischemic brain is an attractant and inducer for the lateral migration of neuroblasts from the SVZ to the injured region.
Yan
Yi-Ping
YP
Department of Neurological Surgery, University of Wisconsin-Madison, WI 53792, United States.
Lang
Bradley T
BT
Vemuganti
Raghu
R
Dempsey
Robert J
RJ
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018960:Hyaluronan Receptors / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D039641:Integrin beta Chains / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009416:Nerve Regeneration / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology
D057134:Antibodies, Neutralizing; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018960:Hyaluronan Receptors; D039641:Integrin beta Chains; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C506897:Spp1 protein, rat; D053495:Osteopontin