188宝金博页面版

Journal of Neurocytology 20, 420-430 Transplanted type-1 astrocytes facilitate repair of demyelinating lesions by host oligodendrocytes in adult rat spinal cord R. J. M. FRANKLIN*, A. J. CRANG and W. F. BLAKEMORE Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK Received 17 September 1990; revised 5 November 1990; accepted 16 November 1990 Summary The ethidium bromide model of demyelination/remyelination provides a system for studying the interactions between demyelinated axons, host glia and transplanted glia. The injection of 0.1% ethidium bromide in isotonic saline into the white matter of the spinal cord produces a glia-free demyelinating lesion which is subsequently remyelinated by Schwann cells and, to a lesser extent, oligodendrocytes. The in vitro description of an oligodendrocyte progenitor isolated from the adult CNS, together with the recognized role of type-1 astroctyes in controlling the developmental programme of perinatal O-2A progenitors, suggested the possibility that transplanted type-1 astrocytes may potentiate oligodendrocyte remyelination of the ethidium bromide lesion. Purified type-1 astrocyte cultures were prepared by removing cells of the oligodendrocyte lineage using a combination of exposure to cytosine arabinoside and complement-mediated immunocytolysis. Following transplantation of purified type-1 astrocyte cultures into ethidium bromide lesions, a significant increase in the extent of oligodendrocyte remyelination was achieved. Because the purified type-1 astrocyte cultures had no demonstrable oligodendrocyte-generating potential it was concluded that the additional oligodendrocytes appearing in the type-1 astrocytes transplanted lesion were of host origin. These results indicate that type-1 astrocytes can facilitate repair of demyelinating lesions by host oligodendrocytes. The possible mechanisms whereby this facilitation occurs are discussed. Introduction Central myelin sheaths are restored to demyelinated axons within the adult CNS in a variety of experimen- tal and naturally occurring conditions (reviewed by Blakemore, 1982; Ludwin, 1987). The limited mitotic potential of mature oligodendrocytes (Ludwin & Bakker, 1988) suggests that extensive remyelination cannot be mediated by these cells but rather by the division, recruitment and differentiation of an oligo- dendrocyte precursor (Ludwin, 1989). Recently, a glial progenitor cell (O-2A adult) which can differentiate into mature oligodendrocytes in vitro has been isolated from the adult rat optic nerve (ffrench-Constant & Raft, 1986; Wolswijk & Noble, 1989; Wolswijk et al., 1990). Such a cell would seem well suited to effect the repair of demyelinating lesions in the adult CNS. Indeed, remyelination following virus-induced de- myelination in mice appears to result from the division and differentiation of O-2A progenitors (Godfraind et al., 1989). In the ethidium bromide (EB) model of demyelin- ation the majority of axons are remyelinated by * To whom correspondence should be addressed Schwann cells and only a small proportion of axons are remyelinated by oligodendrocytes (Gra~a & Blake- more, 1986). Various studies have highlighted the crucial role of the astrocyte in preventing Schwann cell remyelination in the CNS (e.g. Blakemore, 1976; Blakemore & Crang, 1989). The destruction of astro- cytes in the EB lesion results in a situation in which oligodendrocytes must compete with Schwann cells during the repair process. Faced with competition from Schwann cells in the absence of astrocytes, the oligodendrocytes make only a small contribution to the total repair achieved. In vitro studies have revealed the importance of the type-1 astrocyte in controlling the proliferation and differentiation of the O-2A progenitor derived from neonatal rat optic nerve (Noble & Murray, 1984). For example, type-1 astrocytes produce PDGF which is a potent mitogen for the O-2A progenitor (Noble et aI., 1988; Richardson et al., 1988). Type-1 astrocytes might, therefore, be able to promote the adult oligodendro- cyte precursor response during the repair of the EB 0300-4864/91 $03.00 +.12 y 1991 Chapman and Hall Ltd.