Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia

Progenitor cells in the subventricular zone of the lateral ventricle and in the dentate gyrus of the hippocampus can proliferate throughout the life o f the animal. To examine the proliferation and fate of progenitor cells in the subventricular zone and dentate gyrus after focal cerebral ischemia, we measured the temporal and spatial profiles of proliferation of cells and t he phenotypic fate of proliferating cells in ischemic brain in a model of e mbolic middle cerebral artery occlusion in the adult rat. Proliferating cel ls were labeled by injection of bromodeoxyurdine (BrdU) in a pulse or a cum ulative protocol. To determine the temporal profile of proliferating cells, ischemic rats were injected with BrdU every 4 h for 12 h on the day preced ing death. Rats were killed 2-14 days after ischemia. We observed significa nt increases in numbers of proliferating cells in the ipsilateral cortex an d subventricular zone 2-14 days with a peak at 7 days after ischemia compar ed with the control group. To maximize labeling of proliferating cells, a s ingle daily injection of BrdU was administered over a 14-day period startin g the day after ischemia. Rats were killed either 2 h or 28 days after the last injection of BrdU. A significant increase in numbers of BrdU immunorea ctive cells in the subventricular zone was coincident with a significant in crease in numbers of BrdU immunoreactive cells in the olfactory bulb 14 day s after ischemia and numbers of BrdU immunoreactive cells did not significa ntly increase in the dentate gyrus. However, 28 days after the last labelin g, the number of BrdU labeled cells decreased by 90% compared with number a t 14 days. Clusters of BrdU labeled cells were present in the cortex distal to the infarction. Numerous cells immunostained for the polysialylated for m of the neuronal cell adhesion molecule were detected in the ipsilateral s ubventricular zone. Only 6% of BrdU labeled cells exhibited glial fibrillar y acidic protein immunoreactivity in the cortex and subcortex and no BrdU l abeled cells expressed neuronal protein markers (neural nuclear protein and microtubule associated protein-2). From these data we suggest that focal cerebral ischemia induces transient a nd regional specific increases in cell proliferation in the ipsilateral hem isphere and that proliferating progenitor cells may exist in the adult cort ex. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.