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Plasticity in the Adult Human Oligodendrocyte Lineage The Journal of Neuroscience, August 1994, 74(8): 4571-4587 Plasticity in the Adult Human Oligodendrocyte Lineage Nitin Gogate, ‘.a Lalit Verma,l,b Jia Min Zhou,’ Elizabeth Milward,’ Ray Rusten,’ Michael O’Connor,3 Conrad Kufta,* Jin Kim,’ Lynn Hudson,’ and Monique Dubois-Dalcql ‘Laboratory of Viral and Molecular Pathogenesis and *Neurosurgery Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 and 3The Graduate Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Preoligodendrocytes have been described in cultures and [Key words: human brain, oligodendrocytes, regeneration, tissue prints of adult human white matter (Armstrong et al., myelin genes, developmentally regulated genes PDGFaR and 1992). To characterize further these precursors of human MyTl, basic fibroblast growth factor, in situ hybridization] oligodendrocytes, we have investigated whether they ex- press genes playing a critical role in oligodendrocyte de- In the mammalian CNS, oligodendrocytessynthesize the myelin velopment. In the intact human brain, platelet-derived growth sheathsthat enwrap most CNS axons and allow rapid and ef- factor receptor a (PDGFaR) and myelin transcription factor ficient conduction of impulsesalong the nerve tracts (Ritchie, 1 (MyTI) transcripts are expressed in l-2% of cells of the 1984). In demyelinating diseasescaused by viral infection or oligodendrocyte lineage (OL), and clusters of such cells can autoimmune reaction, multifocal lossof myelin results in neu- be found in the periventricular region. Myelin basic protein rological dysfunction of varying severity (Alvord et al., 1992; transcripts containing exon 2 information (exon 2+ MBP), Fazakerley and Buchmeier, 1992). However, oligodendrocytes which are characteristic of the premyelinating stage, are can regenerate, form new myelin sheathsaround the denuded detected in 15-20% of OL cells in vitro. When OL cells are axons, and restore their function (Raine et al., 1988; Ludwin, separated from human white matter and allowed to regen- 1989; Dubois-Dalcq and Armstrong, 1990). This repair process erate in vitro, a much larger proportion of these cells express appears more efficient in rodents than humans, although re- developmentally regulated genes, while exon 2- MBP and myelination can be observed in humansin the months following proteolipid protein (PLP) transcripts characteristic of mature the development of lesionsin multiple sclerosis(MS), a major OL cells appear transiently downregulated. Basic fibroblast neurological diseaseoftemperate countries (Prineaset al., 1993). growth factor (bFGF), even in the presence of PDGF, does To elucidate the mechanismsof regenerationof CNS myelin in not promote DNA synthesis in these cultured OL cells. Yet humans, we studied the biology of the oligodendrocyte lineage bFGF induces human oligodendrocytes to regenerate their of the adult human brain in viva and in vitro. processes rapidly in vitro and to express 04 antigens as The origin of the oligodendrocytes has been extensively stud- well as exon 2+ MBP, MyTI, and PLP transcripts. While bFGF ied in the rat, where they originate from a precursor cell often accelerates early regenerative processes, it also maintains called the O-2A progenitor (Raffet al., 1983; Levison and Gold- high expression of exon 2+ MBP transcripts in OL cells for man, 1993; reviewed in Rat?‘, 1989; Richardson et al., 1990). up to 2 weeks in vitro. In contrast, high levels of insulin in Such progenitors give rise to either oligodendrocytes (0) or type the absence of bFGF allow accumulation of exon 2- MBP 2 astrocytes (2A) in vitro (e.g., Cameron and Rakic, 1991; Hardy and PLP transcripts in most OL cells at 2-3 weeks in vitro. and Reynolds, 1991; Dubois-Dalcq and Armstrong, 1992; Pfeif- We propose that the myelinated human brain harbors a small fer et al., 1993). When O-2A progenitors are grafted in vivo, pool of precursors of oligodendrocytes and that growth fac- they become oligodendrocytes but not type 2 astrocytes (Espi- tor-regulated phenotypic plasticity rather than mitogenic po- nosade Los Monteros et al., 1993). O-2A progenitors have been tential accounts for the regeneration of oligodendrocytes in isolated from all regions of the CNS and they bind antibodies the initial stages of demyelinating diseases such as multiple to a subsetofgangliosides (reviewed in Dubois-Dalcq and Arm- sclerosis. strong, 1992). These progenitor cells are dividing, bipolar, and motile cells that evolve into multipolar progenitors or preoli- Received July 22, 1993: revised Nov. 30, 1993; accepted Jan. 4, 1994. godendroblaststhat can be identified by 04 antibody staining N.G. and L.V. were supported by the Myelin Project, Washington, DC, while performing this work. We thank Dr. Steve Schiff(Children’s Hospital, Washington. (Sommer and Schachner, 198 1; Pfeiffer et al., 1993). Such 04+ DC) and Dr. W. W. Tourtelntte and colleagues (National Neurological Research progenitors then differentiate into oligodendrocytes expressing Specimen Bank, Los Angeles, CA) for supplying the control CNS tissues. Dr. Bill galactocerebroside(GC), the major glycolipid of myelin, and Richardson and Nigel Pringle kindly provided the PDGFaR probes. We are very grateful to Dr. Scott Young for his advice on the in situ hybridization technique, later, the major myelin proteins, MBP and proteolipid protein to Drs. Cedric Raine and Randall McKinnon for advice and permission to cite (PLP) (Dubois-Dalcq et al., 1986, 1987; reviewed in Hudson, their unpublished data, and to Drs. Heinz Arnheiter and Ulrike Tontsch for their 1990) as well as less abundant proteins such as 2’,3’-cyclic critical comments. Editing work was done by Pauline Ballew and Claire Gibson. Correspondence should be addressed to M. Dubois-Dalcq, LVMP, Building 36, nucleotide 3’-phosphohydrolase(CNP). In the adult rodent CNS, Room 5D04. NINDS. NIH, Bethesda, MD 20892. rare “adult” O-2A progenitors reacting with the 04 antibody ,‘Present address: Department of Neurology, University of Maryland, Baltimore, MD. (or preoligodendroblasts)can be isolated from optic nerve, spi- “Present address: School of Medicine, University of Maryland, Baltimore, MD. nal cord, cerebellum,and brain (ffrench-Constantand Raff, 1986; Copyright 0 1994 Society for Neuroscience 0270-6474/94/14457 l-1 7$05,00/O Armstrong et al., 1990a; Hunter and Bottenstein, 1991; Wood 4572 Gcgate et al. * Plasticity in Adult Human Oligodendrocyte Lineage and Bunge, 199 1; Levine et al., 1993). In the optic nerve, adult cytes and their precursors (preoligodendroblasts) but blocks their O-2A progenitors differ from neonatal progenitors by their more differentiation (Eccleston and Silberberg, 1985; McKinnon et complex shape, slower cell cycle, and migration speed in vitro al., 199 I), while insulin-like growth factor I (IGF-I) promotes (Wolswijk and Noble, 1989; Wren et al., 1992). Such cells can oligodendrocyte survival and development and enhances my- divide and generate new oligodendrocytes following demyelin- elination in transgenic mice (McMorris et al., 1986; McMorris ation in rodents (Ludwin. 1979; reviewed in Dubois-Dalcq and and Dubois-Dalcq, 1988; Barres et al., 1992; Carson et al., Armstrong, 1990). 1993). In cultures of adult rat CNS, O-2A progenitors divide in Much less is known about the development and regeneration response to bFGF and PDGF alone or in combination (Wol- of the oligodendrocyte lineage in human. As subcortical white swijk et al., 199 1, 1992; Vick and DeVries, 1992), while oli- matter is sometimes removed in neurosurgical procedures for godendrocytes can divide in response to neuronal signals (Wood focal lesions not affecting white matter, cultures enriched in and Bunge, 1986). In contrast, in cultures of adult human brain, human oligodendrocytes can be prepared from fresh CNS tissue neither preoligodendrocytes (corresponding to the adult rat O-2A (Armstrong et al., 1992; Yong and Antel, 1992). 04+ GC- progenitor) nor oligodendrocytes respond to PDGF and/or bFGF cells (called preoligodendrocytes; see below) were recently iden- by mitosis (Yong et al., 1988; Armstrong et al., 1992). The tified in such cultures and shown to progressively differentiate human 04+ GC- precursor was therefore named preoligo- into oligodendrocytes (Armstrong et al., 1992). Rare cells re- dendrocyte rather than preoligodendroblast. bFGF favors the acting only with the 04 antibody were also detected in tissue human preoligodendrocyte phenotype in vitro while IGF-I pro- prints of human white matter (Armstrong et al., 1992). While motes differentiation of human oligodendrocytes (Armstrong et antibodies to glycolipids allow clear identification of oligoden- al., 1992). There has been no report so far that the adult human drocyte progenitors in the nonmyelinated developing CNS CNS harbors cells with properties of the rat O-2A neonatal (Warrington et al., 1993) their use on sections of myelinated progenitor cells. white matter is less reliable and the exact function of these Here we present evidence that the human myelinated brain glycolipids in oligodendrocyte development is unknown. contains a discrete pool of oligodendrocyte precursor cells ex- We have therefore chosen to study the expression of genes pressing PDGFcvR and MyTI while a larger subpopulation of that are developmentally regulated in precursor cells of the hu- glial cells expresses exon 2+ MBP transcripts. These transcripts man oligodendrocyte lineage (OL). One gene involved in a sig- are more widely
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