Adult Spinal Cord Stem Cells Generate Neurons after Transplantation in the Adult Dentate Gyrus

Abstract

The adult rat spinal cord contains cells that can proliferate and differentiate into astrocytes and oligodendroglia in situ. Using clonal and subclonal analyses we demonstrate that, in contrast to progenitors isolated from the adult mouse spinal cord with a combination of growth factors, progenitors isolated from the adult rat spinal cord using basic fibroblast growth factor alone display stem cell properties as defined by their multipotentiality and self-renewal. Clonal cultures derived from single founder cells generate neurons, astrocytes, and oligodendrocytes, confirming the multipotent nature of the parent cell. Subcloning analysis showed that after serial passaging, recloning, and expansion, these cells retained multipotentiality, indicating that they are self-renewing. Transplantation of an in vitro-expanded clonal population of cells into the adult rat spinal cord resulted in their differentiation into glial cells only. However, after heterotopic transplantation into the hippocampus, transplanted cells that integrated in the granular cell layer differentiated into cells characteristic of this region, whereas engraftment into other hippocampal regions resulted in the differentiation of cells with astroglial and oligodendroglial phenotypes. The data indicate that clonally expanded, multipotent adult progenitor cells from a non-neurogenic region are not lineage-restricted to their developmental origin but can generate region-specific neurons in vivo when exposed to the appropriate environmental cues.Key words : spinal cord; stem cells; FGF; transplantation; neuroplasticity; adult Most neurogenesis in the mammalian CNS is believed to end in the period just after birth (Nornes and Das, 1974;Altman and Bayer, 1984). However, neurogenesis continues in different regions of the brain of various adult mammalian species (Kaplan and Hinds, 1980;Bayer et al., 1982; Alvarez-Buylla, 1993, 1994;Luskin, 1993). The spinal cord, like most structures of the mammalian brain, belongs to the class of nonrenewable epithelium (Rakic, 1985). However, a small number of cells that line the central canal (Adrian and Walker, 1962;Johansson et al., 1999) remain mitotic. We have demonstrated recently that the adult rat spinal cord contains large numbers of dividing cells in vivo that give rise to glia but not neurons (Horner et al., 2000).Multipotent stem cells that respond to epidermal growth factor (EGF) or basic fibroblast growth factor (FGF-2) have been isolated from both neurogenic (Morshead et al., 1994;Palmer et al., 1997) and non-neurogenic regions of the adult mammalian CNS (Temple and Alvarez-Buylla, 1999). Recent studies indicate that embryonic day 14 mouse striatum or adult subventricular zone (SVZ) contains multipotent stem-like cells that are controlled by FGF-2 or EGF in a regulatable manner (Ciccolini and Svendsen, 1998;Gritti et al., 1999). However, this is not true of adult CNS stem cells from all regions, because a combination of EGF and FGF-2 was necessary to isolate stem cells from the adult mouse spinal cord ,...

Transcription Factor Expression and Notch-Dependent Regulation of Neural Progenitors in the Adult Rat Spinal Cord

“…Thus, our results suggest the common control mechanisms for adult and embryonic progenitors. Neural stem cells are present in both the adult and embryonic spinal cord (Weiss et al, 1996;Kalyani et al, 1997;Johansson et al, 1999;Shihabuddin et al, 2000). We also identified bipotential progenitors in our cultures, although it was not determined whether these cells possessed the properties of bona fide stem cells.…”

“…Neural stem cells and other types of progenitors are also present in some nonperiventricular regions (Palmer et al, 1995(Palmer et al, , 1999Marmur et al, 1998;Kondo and Raff, 2000). Adult spinal cord also contains progenitors for neurons and glia (Weiss et al, 1996;Kehl et al, 1997;Shihabuddin et al, 1997Shihabuddin et al, , 2000Johansson et al, 1999;. However, the precise locations and details of the heterogeneity of adult progenitors in each region still remain poorly understood (Morshead and van der Kooy, 2001).…”

Une nouvelle zone de neurogenèse fonctionnelle

“…Certaines régions dans lesquelles l'existence d'une neurogenèse est controversée ont été omises par souci de simplicité. ccme : canal central de la moelle épinière ; ctx : cortex ; cvd : complexe vagal dorsal ; fh : formation hippocampique ; gd : gyrus dentelé de l'hippocampe ; hyp : hypothalamus ; vl : ventricule latéral ; bo : bulbe olfactif ; fmr : flux migratoire rostral ; zsg : zone sous-granulaire (du gyrus dentelé) ; zsv : zone sous-ventriculaire ; str : striatum ; 4v : IV e ventricule ; nv : noyaux vestibulaires (modifié d'après [7] 4 , inclinaison de la tête du côté lésé, asymétrie du tonus des muscles des membres, élargissement de la surface de sustentation, nausées) (Figure 2) résultent de l'asymétrie de l'activité électrique spontanée entre les noyaux vestibulaires (NV) homologues situés dans le tronc cérébral. En effet, consécutivement à l'atteinte vestibulaire, les NV ipsilatéraux à la lésion deviennent silencieux tandis que les NV controlatéraux conservent une activité électrique.…”

“…Les ventricules cérébraux hébergent des progéniteurs neuraux qui conserveraient au stade adulte leur capacité de proliférer et de se différencier en divers types neuronaux ou gliaux [4,22]. Les NV, situés en bordure du IV e ventricule, pourraient donc héberger des progéniteurs neuraux quiescents puisque chez le mammifère adulte, en conditions physiologiques, aucune prolifération cellulaire spontanée ne survient dans cette zone cérébrale.…”

“…Ainsi, des progéniteurs neuraux de la zone sous-granulaire ou de la zone sousventriculaire transplantés dans des zones non neurogènes meurent ou s'y différencient uniquement en cellules gliales [2][3][4]. En revanche, lorsque des progéniteurs provenant de n'importe quelle région du SNC sont transplantés dans des zones de neurogenèse, ils s'y différencient selon le type neuronal requis par le tissu hôte, neurones granulaires dans la zone sous-granulaire et interneurones dans la zone sous-ventriculaire [3][4][5][6]. Il apparaît donc que le devenir des progéniteurs neuraux au sein de leur tissu hôte est avant tout commandité par l'environnement extracellulaire, au détriment des paramètres intrinsèques aux cellules [7,8].…”