Increased Dentate Neurogenesis After Grafting of Glial Restricted Progenitors or Neural Stem Cells In The Aging Hippocampus

¹ Department of Surgery (Neurosurgery), Duke University Medical Center, Durham NC 27710; Medical Research and Surgery Services, VA Medical Center, Durham NC 27705
² Stem Cell Unit, LNS, National Institute for Aging, NIH, Baltimore, MD 21224
³ Invitrogen, Corporate Research Laboratories, Carlsbad, CA 92008

^* To whom correspondence should be addressed. E-mail: Ashok.Shetty{at}Duke.Edu.

	Abstract

Neurogenesis in the dentate gyrus (DG) declines severely by middle age, potentially owing to age-related changes in the DG microenvironment. We hypothesize that providing fresh glial restricted progenitors (GRPs) or neural stem cells (NSCs) to the aging hippocampus via grafting enriches the DG microenvironment and thereby stimulates the production of new granule cells from endogenous NSCs. The GRPs isolated from the spinal cords of embryonic day 13.5 transgenic F344 rats expressing human alkaline phosphatase gene, and NSCs isolated from embryonic day 9 caudal neural tubes of Sox-2:EGFP transgenic mice were expanded in vitro and grafted into the hippocampi of middle-aged (12-months old) F344 rats. Both types of grafts survived well, and grafted NSCs in addition migrated to all layers of the hippocampus. Phenotypic characterization revealed that both GRPs and NSCs differentiated predominantly into astrocytes and oligodendrocytic progenitors. Neuronal differentiation of graft-derived cells was mostly absent except in the dentate subgranular zone (SGZ) where some of the migrated NSCs but not GRP's differentiated into neurons. Analyses of the numbers of newly born neurons in the DG using 5'-bromodeoxyuridine and/or doublecortin assays however, demonstrated considerably increased dentate neurogenesis in animals receiving grafts of GRPs or NSCs, in comparison to both naïve controls and animals receiving sham-grafting surgery. Thus, both GRPs and NSCs survive well, differentiate predominantly into glia, and stimulate the endogenous NSCs in the SGZ to produce an increased number of new dentate granule cells following grafting into the aging hippocampus. Grafting of GRPs or NSCs therefore provides an attractive approach for improving neurogenesis in the aging hippocampus.

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