Adult neurogenesis and neural stem cells of the central nervous system in mammals

Abstract

Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate neurons, astrocytes, and oligodendrocytes in the nervous system (Fig. 1a). Over the past decades, the confirmation that neurogenesis occurs in discrete areas of the adult brain and that NSCs reside in the adult brain has overturned the long-held dogma that we are born with a certain number of nerve cells and that the brain cannot generate new neurons and renew itself. In this article, we review the evidence that neurogenesis occurs in the adult mammalian central nervous system (CNS) and that the adult CNS contains NSCs. Neurogenesis and neural stem cells of the adult mammal central nervous system. a: Neural stem cells (NSCs) are self-renewing, multipotent cells that generate cells of the neuronal lineage: neurons, astrocytes and oligodendrocytes. b: Sagittal representation of the two neurogenic areas of the adult CNS: the olfactory bulb (OB) and the dentate gyrus (DG) of the hippocampus. The new neuronal cells in the OB are generated from NSCs of the subventricular zone (SVZ). The SVZ is a narrow zone of tissue in the wall of the lateral ventricle in the forebrain. The NSCs of the SVZ migrate to the OB via the rostro-migratory stream (RMS), where they differentiate into interneurons of the OB. c: There are two conflicting theories regarding the cellular origin of the NSCs of the adult SVZ (c). In one, the NSCs of the SVZ are differentiated ependymal cells. Ependymal cells are specialized, ciliated cells that line the ventricle wall. In the other, they are astrocyte-like cells expressing glial fibrillary acidic protein in the SVZ. d: The new neuronal cells in the adult DG are generated from NSCs of the subgranular zone (SGZ) of the hippocampus and differentiate into neural and glial cells in the granular layer of the DG. The first evidence that neurogenesis occurs in certain regions of the adult mammalian brain came from [3H]-thymidine labeling studies conducted by Altman and Das (1965). In the 1990s, new methods for labeling dividing cells, such as retroviral virus and bromodeoxyuridine (BrdU), a marker of the S-phase of the cell cycle, were introduced to study neurogenesis in the adult central nervous system (CNS) (Corotto et al., 1993; Luskin, 1993; Seki and Arai, 1993). These studies helped to confirm that neurogenesis occurs in the adult mammalian brain and that new neurons are generated continuously in some regions of the adult CNS. Neurogenesis has been shown to occur throughout adulthood in two neurogenic areas of the adult mammalian CNS: the olfactory bulb (OB) and the dentate gyrus (DG) of the hippocampus (Fig. 1b). Low levels of neurogenesis have also been reported in the Ammon's horn of the adult mouse (Rietze et al., 2000). Previous studies have shown that neurogenesis occurs in the OB of adult rodents (Altman, 1969; Bayer, 1983; Kaplan et al., 1985; Kishi, 1987; Corotto et al., 1993; Lois and Alvarez-Buylla, 1994) and non-human primates (Kornack and Rakic, 2001a,b). The new neuronal cells in the adult mammalian OB are generated from neural progenitor cells (NPCs) in the anterior part of the subventricular zone (SVZ) (Fig. 1c) (Luskin, 1993; Type C cells, Doetsch et al., 1997). The SVZ is a narrow zone of tissue in the wall of the lateral ventricle in the forebrain. The NPCs of the SVZ migrate to the OB via the rostro-migratory stream (RMS; Type A cells, Doetsch et al., 1997), where they differentiate into interneurons of the OB: granule cells and periglomerular cells (Altman, 1969; Corotto et al., 1993; Luskin, 1993; Lois and Alvarez-Buylla, 1994). Neurogenesis also occurs in the adult DG of the hippocampus of rodents (Altman and Das, 1965; Kaplan and Hinds, 1977; Bayer et al., 1982; Kaplan and Bell, 1983,1984; Seki and Arai, 1993; Cameron et al., 1993a; Kuhn et al., 1996; Kempermann et al., 1997a), humans (Eriksson et al., 1998) and non-human primates (Kornack and Rakic, 1999; Gould et al., 2001). The NPCs of the adult DG are generated in the subgranular zone (SGZ) of the DG and differentiate into neuronal and glial cells in the granular layer of the DG (Fig. 1d; Cameron et al., 1993). Retrograde tracing studies have shown that the newly generated neuronal cells extend axons into the CA3 region of the hippocampus, (Stanfield and Trice, 1988; Markakis and Gage, 1999) as soon as 4–10 days after mitosis (Hastings and Gould, 1999). They receive synaptic input (Kaplan and Bell, 1983; Markakis and Gage, 1999) and project functional connections in vitro (Song et al., 2002) and in vivo to the CA3 region (van Praag et al., 2002). The evidence that neurogenesis occurs in the adult mammalian forebrain raised the question of the existence of NSCs in the adult CNS. The fact that a cell can be labeled in vivo by administration of [3H]-thymidine or BrdU, or by retroviral labeling, does not mean that it is a stem cell; thus NSC research has focused on identifying the NSCs of the adult CNS. The first cells from the adult CNS charac