Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation
Introduction
During early development, oligodendrocyte progenitor cells are generated in the restricted region of the ventral ventricular zone (Warf et al., 1991, Noll and Miller, 1993, Pringle and Richardson, 1993, Ono et al., 1995), but during late gestational and early postnatal development, glial progenitor cells exist in the subventricular zone (SVZ) (Paterson et al., 1973, Sturrock, 1976, Levison and Goldman, 1993) and migrate into the intermediate zone and cortical plate where they differentiate into immature oligodendrocytes, which subsequently further mature and myelinate axons (LeVine and Goldman, 1988a, LeVine and Goldman, 1988b, Hardy and Reynolds, 1991, Ellison et al., 1996). Oligodendrocyte progenitor cells, however, exist in the adult rodent SVZ (Levison et al., 1999) and subcortical white matter (Genser and Goldman, 1996, Genser and Goldman, 1997, Zhang et al., 1999), and even in the adult human white matter (Armstrong et al., 1992, Roy et al., 1999). Interestingly, such cells have also been reported in patients with multiple sclerosis (MS) (Wolswijk, 1998) and in rodents with chronic experimental allergic encephalomyelitis (Nishiyama et al., 1997). Though the presence of oligodendrocyte progenitor cells in the adult brain has not been fully accepted yet, these observations suggest that the remyelination process occurs in both physiological and pathological conditions, in the adult brain. In human demyelinating diseases such as MS, oligodendrocyte progenitors may divide and/or migrate in response to signals present in demyelinated lesions and thus facilitate remyelination (Armstrong et al., 1992, Roy et al., 1999). Regardless of the progenitor's presence in the lesions in demyelinating diseases, the remyelination process does not fully occur in such cases. The deficiency of repair in such demyelinating disorders may be improved by stimuli to enhance oligodendrocyte maturation. One such strategy is to promote survival of oligodendrocytes, or maturation of oligodendrocytes formed from progenitors, to extend their processes to wrap axons (Oh and Yong, 1996). This approach to enhance the extent of process formation has been documented around the edges of lesions in the MS (Prineas et al., 1989, Prineas et al., 1993, Raine and Wu, 1993, Raine et al., 1981).
The maturation of oligodendrocytes is regulated by growth factors (Bögler et al., 1990, Gard and Pfeiffer, 1993, McKinnon et al., 1993, Wolswijk and Noble, 1992, Barres et al., 1992, Barres et al., 1993, McMorris and Dubois-Dalcq, 1988), cytokines (Mayer et al., 1994) and the extracellular matrix (Oh and Yong, 1996). Cell–cell interactions also may play important roles in the maturation of oligodendrocytes. Axons control oligodendrocyte survival (Barres and Raff, 1999). Contact with central nervous system (CNS) myelin inhibits oligodendrocyte progenitor maturation (Robinson and Miller, 1999). We (Sakurai et al., 1998) and others (Bhat and Pfeiffer, 1986, Gard et al., 1995, Oh and Yong, 1996) reported previously that oligodendrocyte maturation in vitro is promoted by astrocytes, and astrocytes are involved in early events of myelinogenesis in vivo. Furthermore, abnormalities in the astroglia of the dysmyelinating Jimpy mouse may inhibit oligodendroglial cell development and myelination (Skoff, 1976). A soluble factor present in the extracts of astrocyte-enriched cultures enhances the expression of myelination-associated events (Bhat and Pfeiffer, 1986). Platelet-derived growth factor and leukemia inhibitory factor are mediators of astrocyte function as paracrine regulators of oligodendroblast and oligodendrocyte survival (Gard et al., 1995), and basic fibroblast growth factor (bFGF) is one of the candidates for the maturation factor released from astrocytes (Oh and Yong, 1996).
Erythropoietin (Epo) is a cytokine that acts in erythroid progenitor proliferation and differentiation. Recently, it has been reported that Epo is produced in astrocytes (Masuda et al., 1994), and protects hippocampal and cortical neurons against glutamate neurotoxicity in vitro (Morishita et al., 1997) or cerebral ischemia in vivo (Sakanaka et al., 1998, Brines et al., 2000). Both immunohistochemical localization and mRNA expression of Epo and its receptor change during development (Liu et al., 1994, Chin et al., 2000, Juul et al., 1998, Juul et al., 1999), suggesting that Epo may play important roles in development of the brain. The actions of Epo on glia cells, however, have not been investigated in detail. In this study, therefore, we examined whether Epo is one of the astrocyte-derived factors that cause oligodendrocyte maturation in vitro, using primary cultured late stage immature oligodendrocytes from the rat cerebral hemisphere.
Section snippets
Cell culture
All experimental protocols were approved by the Tokyo Metropolitan Institute of Gerontology Animal Care and Use Committee according to the protocol of the Institute of the Health Animal Care and Use. The cerebral hemispheres were isolated from pregnant or neonatal rats under the control of anesthesia using diethyl ether. The purity of neural cells (O4-positive oligodendrocytes, glial fibrillary acidic protein (GFAP)-positive astrocytes, neurofilament-positive neurons) used in this experiment
Epo/Epo-R expression
To determine whether the glial cells cultured from the embryonic brain express Epo or Epo-R, the expression of Epo/Epo-R was examined at the mRNA level by RT-PCR. The late stage immature oligodendrocytes were cultured for 3 days after the last passage (Section 2). The levels of expression of Epo mRNA (325 bp) in oligodendrocytes were much higher than those in neurons or astrocytes, which were the same as those in the young adult kidney (Fig. 1A). On the other hand, the levels of Epo-R mRNA were
Expression of Epo and its receptor in glia cells
Epo-R expression in the CNS has been reported to be abundant in the embryonic, fetal and adult brain (Digicaylioglu et al., 1995, Marti et al., 1996, Morishita et al., 1997, Liu et al., 1997, Juul et al., 1998). Binding studies using radiolabeled Epo showed that specific binding sites of Epo are present in some defined areas of the adult mouse brain, including the hippocampus and cerebral cortex, in which neurons highly vulnerable to ischemia are present (Digicaylioglu et al., 1995). The
Conclusions
We found that Epo enhances the maturation of oligodendrocytes and proliferation of astrocytes. These comprehensive effects of Epo might also affect the ability of oligodendrocyte lineage cells to promote myelin repair in human demyelinating diseases, such as MS and white matter disease.
Acknowledgements
We thank Dr M. Higuchi (Chugai Pharmaceu. Co. Ltd) for generously donating anti-Epo antibody and soluble Epo-R and for helpful advice, Dr R. Sasaki (Shiga Prefecture University), Dr S. Masuda (Kyoto University), Dr T. Neichi (Chugai Pharmaceu. Co. Ltd) and Dr N. Imai (Chugai Pharmaceu. Co. Ltd) for helpful discussion.
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Present address: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-13, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.