Adult-Derived Neural Precursors Transplanted into Multiple Regions in the Adult Brain Daniel G. Herrera, MD, PhD,* Jose Manuel Garcia-Verdugo, PhD,† and Arturo Alvarez-Buylla, PhD‡ Neural stem cells persist in the adult brain subventricular zone (SVZ). These cells generate a large number of new neurons that migrate to the olfactory bulb, where they complete their differentiation. Here, we transplanted cells carrying -galactosidase under the control of neuron-specific enolase promoter (NSE::LacZ) from the SVZ of adult mice into the striatum cortex and olfactory bulb, with or without an excitotoxin lesion. Between 2 and 8 weeks after transplantation, grafted cells were present in the recipient regions, but extensive migration and differentiation into mature neurons of grafted cells were only observed in the olfactory bulb. Clusters of graft-derived neuroblasts forming chain-like structures were observed within or close to the grated sites in the cortex and striatum; electron microscopy confirmed that graft- derived cells in the olfactory bulb and a small number in the striatum were neurons. Surprisingly, most of the cells expressing NSE::LacZ outside the olfactory bulb were astrocytes. We conclude that primary precursors from the SVZ migrate and differentiate effectively only within the environment of the olfactory bulb. Only limited survival and dif- ferentiation were observed in other brain regions studied. Herrera DG, Garcia-Verdugo JM, Alvarez-Buylla A. Adult-derived neural precursors transplanted into multiple regions in the adult brain. Ann Neurol 1999;46:867– 877 The adult brain has a limited capacity for self-repair after neuronal loss caused by trauma or disease. Inter- estingly, work over the past four decades has shown that new neurons continue to be born, migrate, and differentiate within certain regions of the adult verte- brate brain. 1–9 Studies in vitro have demonstrated that neural stem cells (ie, cells that can self-renew and gen- erate astrocytes, oligodendrocytes, and neurons) are present in the adult mammalian brain. 7,10,11 The subventricular zone (SVZ), which is located be- neath the ependymal lining of the lateral ventricles, contains the largest pool of neuronal precursors in the adult brain. 3,12 These neuroblasts migrate through the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. 4,13 The SVZ persists into adulthood in all mammals stud- ied, 14 –18 and recent work suggests that neuronal pre- cursors persist in the periventricular tissue of the tem- poral pole of the adult human brain. 9 Neuronal replacement by transplantation offers a promising treatment for neurodegenerative disorders, 19,20 and SVZ cells could serve as an important source of neu- ronal precursors for transplantation. When grafted into the embryo, mouse SVZ precursors ranging in age from postnatal day 5 to postnatal day 10 integrate into multiple locations within the brain. 21 Neonate-derived SVZ cells can migrate and differentiate into neurons when grafted into the neonatal or adult striatum. 22,23 The potential after transplantation of adult-derived SVZ precursors has not been tested, however. In this study, we followed the fate of SVZ cells iso- lated from the adult brain and grafted into the stria- tum, cortex, hippocampus, and olfactory bulb of the adult brain. We asked whether (1) adult-derived SVZ neural precursors can survive and differentiate into neurons in adult mouse brain regions other than the olfactory bulb, (2) there is preferential survival and dif- ferentiation of SVZ cells in a lesioned area, and (3) migration of SVZ cells differs in the different trans- plantation sites. We used genetically tagged SVZ cells to follow the fate of grafted cells. Methods Animal Procedures One hundred twenty-four male CD-1 mice (2–3 months old) were used as hosts for these experiments. Donors were From the *Departments of Psychiatry and Neurology and Neuro- science, The New York Hospital, Cornell Medical Center, and ‡De- partment of Neurology, Rockefeller University, New York, NY; and †Universidad de Valencia, Valencia, Spain. Received Nov 6, 1998, and in revised form Jun 1, 1999. Accepted for publication Jul 9, 1999. Address correspondence to Dr Alvarez-Buylla, Department of Neu- rology, Rockefeller University, 1203 York Avenue, Box 210, New York, NY 10021. Copyright © 1999 by the American Neurological Association 867