Demyelination and Remyelination after Spinal Cord Injury

JOURNAL OF NEUROTRAUMAVolume 23, Number 3/4, 2006© Mary Ann Liebert, Inc.Pp. 345–359

Demyelination and Remyelination after Spinal Cord Injury

JOHN W. MCDONALD and VISAR BELEGU

ABSTRACT

Since the discovery in the 1960s that remyelination can occur in the damaged central nervous sys-tem (CNS) (Bunge et al. 1961), there has been much progress in understanding the cellular and mo-lecular biology of oligodendroglia and the factors that regulate their propagation, migration, dif-ferentiation, maturation, and ability to myelinate nerve axons. More recently, greater understandingof disease states and the role of oligodendrocytes in remyelination have sparked tremendous inter-est in this once obscure field. Although the explosion of information is being hampered by adher-ence to commonly held beliefs based on empirical evidence, novel molecular and cellular tools areallowing scientists to address age-old assumptions. It is now recognized that, as well as promotingsalutatory conduction along axons, oligodendroglia are important near-term clinical targets forrestoring function after CNS injury, particularly spinal cord injury. Thus, remyelination appearsto be one of the most feasible restoration strategies. This review focuses on concepts that are im-portant for developing strategies of repair. The brightest young scientists will be attracted into thisexciting field by its near-term potential for human application.

Key words: activity dependence; oligodendrocytes; progenitors; remyelination; spinal cord injury

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International Center for Spinal Cord Injury, Kennedy Krieger Institute and the Johns Hopkins University School of Medicine,Baltimore, Maryland.

INTRODUCTION

THE AXONS OF MANY NERVE FIBERS are wrapped in awhite insulating sheath called “myelin,” whose func-

tions are not fully understood. Although myelinated nervefibers were discovered in 1833 (Table 1), there is stillmuch to be learned about myelination, which is per-formed by Schwann cells in the peripheral nervous sys-tem and oligodendrocytes in the central nervous system(CNS). Among the most pressing questions are the fol-lowing: How many oligodendrocyte progenitors are gen-erated in the adult spinal cord every hour? How manydie every hour? How many oligodendrocytes are there inthe spinal cord or the entire CNS? Are most oligoden-

drocytes located in gray or white matter? What are theroles of these resident progenitor cells? What percentageof long-tract axons is unmyelinated in the spinal cord?Why are these axons not myelinated? Many questionsabout remyelination of injured nerve axons remain aswell. Does normal remyelination occur after injury? Ifthis occurs, what cell is responsible for this process? Isthis cell also responsible for the dysmyelination that isseen after injury? What events regulate remyelination atthe cellular and molecular level?

Several scenarios have been suggested for remyelina-tion. However, despite exciting progress in the field ofregeneration widespread functional remyelination has notbeen demonstrated in the adult injured CNS. The focus

of this review is on advances in myelin biology over thelast quarter century. Studies of Schwann cells have beenwell reviewed (Bunge and Pearse, 2003).

OLIGODENDROCYTE LINEAGE

Before the advent of immunohistochemistry, electronmicroscopy was used to identify oligodendrocytes, whosetypical ultrastructural features include distinguishedbranching of the cytoplasm that form a segment of sheath-ing around a neuronal axon. Identification of these cellstoday is based largely on the differential expression ofinternal and cell-surface markers, while functional andanatomical characteristics help further define subtypes.However, modern immunological methods for identify-ing oligodendroglia are based largely on in vitro studiesand should be applied cautiously in vivo. Thus, in vivorecognition should involve immunohistochemistry com-bined with tract-specific anatomical characteristics. Fig-ure 1 illustrates the oligodendroglial lineage and gives

examples of immunological markers that are useful invitro and in vivo. There are excellent reviews of the mol-ecular, cellular, and electrophysiological properties ofoligodendrocyte progenitors (Baumann and Pham-Dinh,2001; Dawson et al., 2000; Lin and Bergles, 2002).

IMPORTANT DEVELOPMENTAL,PHYSIOLOGICAL, AND ANATOMICALCONSIDERATIONS IN MYELINATION

The myelin sheath has become progressively moreprominent during the course of evolution. Thus, glial cellsrepresent 25% of the total cells in the CNS in Drosophila,65% in rodents, and 90% in humans (Baumann andPham-Dinh, 2001). Oligodendrocytes and myelinationare special adaptations in higher vertebrates, whose cor-tical area has been increased by folding. Myelination al-lows information to be transmitted accurately from oneneuron to another even though folds (folia) in the brainresult in axons of different lengths.

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TABLE 1. LANDMARK STUDIES OF MYELINATING CELLS

Date Discovery Reference

1833 Myelinated nerve fibers Ehrenberg, 18371846 “Nervenkitt” � nerve glue (neuroglia) Virchow, 18461858 Thinking that myelin was inside nerve fibers, Virchow coined the term Virchow, 1858

“myeline,” from the Greek “myelos,” which means “marrow.”1871 Noted that myelin sheaths have periodic disruptions Ranvier, 18711909 Reasoned that axons secrete myelin Cajal, 19091928 Proposed the term “oligodendroglia” to describe neuroglia that show Rio Hortega, 1928

few processes in metal-impregnated tissue1930s The concept that myelin associates with oligodendroglia emerged. Pennfield, 19321930s Salutatory conduction and periodicity became accepted, a century after Huxley and Stampell, 1949;

and 1940s they were proposed. Tasaki, 19391954 Spiral wrapping of axons by Schwann cells in the peripheral nervous Geren, 1954

system was recognized.1960 Spiral wrapping of axons by oligodendrocytes in the central nervous Maturana, 1960; Peters, 1960

system was recognized.1960/61 Showed that demyelinated axons in adult cats can be remyelinated Bunge et al., 1960, 19611960s Showed that the adult central nervous system (CNS) can generate Altman, 1962; Altman and

oligodendrocytes Bayer, 19841968 Demonstrated that a single oligodendrocyte, unlike a single Schwann Bunge, 1968

cell, can myelinate many segments on different axons1970s Showed that oligodendrocyte regeneration and myelination involve Herndon et al., 1977;

immature oligodendrocytes Ludwin, 19791972 Computer simulation suggested that salutatory conduction could occur Koles and Rasminsky, 1972

when an axon’s sheath is as thin as 3% of its normal size but thatconduction is disrupted by loss of myelin from a single internode.

1979 Showed that remyelination restores normal conduction in the CNS Smith et al., 19791983 Transplanted oligodendrocytes from newborn mouse CNS to adult Gumpel et al., 1983

newborn mice brains; remyelinated host axons

The brain’s subventricular zone (SVZ), which formsin the late gestational and early postnatal periods in mam-mals, is a major source of oligodendrocytes. In the mouse,it enlarges during the peak of gliogenesis, between P5and P20, and then shrinks to persist throughout adult life(Baumann and Pham-Dinh, 2001; Doetsch et al., 1997).Gliogenesis and myelination are tightly orchestratedwithin a single tract. In the mouse, myelination starts atbirth in the spinal cord and is complete in most areas ofthe brain 45–60 days postnatally. In humans, it begins asearly as the second half of fetal life in the spinal cord andpeaks in the first postnatal year. Myelination can con-tinue through the second decade of life in intracorticalfibers, especially in associative areas (Baumann andPham-Dinh, 2001; Van Der Knaap and Valk, 1995).

Oligodendrocyte precursors generated in the SVZ mi-grate long distances to populate the developing CNS,forming white matter (Baumann and Pham-Dinh, 2001;Garcia-Verdugo et al., 1998). Birth and differentiation ofoligodendrocyte precursors in the spinal cord occurs firstin a rostral to caudal gradient, regulated by retinoic acid.Later they occur in a dorsal to ventral gradient, and areregulated in part by sonic hedgehog (Bongarzone, 2002;Glover, 2000).

Oligodendrocyte birth is largely complete by the on-set of myelination, which usually starts postnatally (Skoff

et al., 1976). However, oligodendrocyte progenitors con-tinue to be born throughout life and proliferate after CNSinjury, though the significance of these processes is un-clear (Horner et al., 2000). Although the central canal isan important source of early oligodendrocyte progenitors,these cells are rapidly recruited from a transient popula-tion of progenitors resident in the local gray and whitematter throughout the spinal cord if the cord is injured.

Differentiation of oligodendrocyte precursors is regu-lated by growth factors (PDGF, NT-3, BDNF, CNTF,bFGF), Notch signaling, substrate signaling, chemokines,and other possible mechanisms (Baumann and Pham-Dinh, 2001; David and Lacroix, 2003; Horner and Gage,2000; Tsai et al., 2002). Once differentiation occurs,oligodendrocytes lose their ability to migrate. Thus, pre-mature differentiation limits oligodendrocyte migrationand integration after injury or transplantation.

Generally, each mature oligodendrocyte can myelinatefrom one to 60 different axonal segments (Remahl andHildebrand, 1990). Oligodendrocytes that myelinatethick axons tend to myelinate few segments, whereasthose that myelinate thin axons myelinate many seg-ments. Surprisingly, the latter myelinate only about 10%of the axons within their reach (up to 360 �m2), and theynever myelinate two contiguous segments of a singleaxon or all the axons within close reach. It is unclear

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OligodendrocytePrecursor Cell(A)

Nestin+

PSA-NCAM+

PDRGFRα+

O4–

OligodendrocyteProgenitor Cell(B)

A2B5+

NG2+

PDRGFRα+

GD3+

O4–

Non-MyelinatingMatureOligodendrocyte

(D)

O1+

RIP+

GalC+

MBP+

PLP+

MAG+

Terminallly MatureOligodendrocyte(E)

O1+

RIP+

GalC+

MBP+

PLP+

MAG+

0Mgp+

Pre-Oligodendrocyte(C)A2B5+

GD3+

NG2PDRGFRα+

O4+

FIG. 1. Oligodendrocyte lineage. Morphological and antigenic progression from oligodendrocyte precursor cells (A), oligo-dendrocyte progenitor cell (B), pre-oligodendrocyte (C), non-myelinating mature oligodendrocyte (D), and terminally matureoligodendrocyte (E). Stage-specific markers and absence of markers are indicated within boxes (adapted from Baumann andPham-Dinh, 2001; Lubetzki et al., 1997).

whether oligodendrocytes myelinate axons in a concor-dant or discordant manner with regard to axonal activity,though the latter seems the most likely because the lossof single oligodendrocytes would not grossly alter nervefunction.

A critical concept for understanding myelination andremyelination is the great dependence of gliogenesis andmyelination on neural activation. Previous data from therat and mouse optic nerve correlated proliferation ofoligodendrocyte precursor cells with axonal electrical ac-tivity (Barres and Raff, 1993). More recent data suggestthat axonal activity has a stronger influence on myelina-tion, however (Barres and Raff, 1999; Demerens et al.,1996).

The timing of myelination varies greatly in differentpathways. Pathways such as those in the spinal cord thatmyelinate early in development will have to cope withup to a 40-fold increase in axonal length by the time theCNS neuron reaches adult size. In contrast, late myeli-nating pathways, such as those in the cortex, will haveto cope with only a doubling in axonal length. As a re-sult, early myelinating pathways have a 1:1 ratio of oligo-dendrocytes to axons, and internode lengths can be up to1 mm in length. Late myelinating pathways have oligo-dendrocyte to axonal segment ratios of up to 1:60, andinternodes are only 40–60 �m long. Therefore, responseto injury is expected to vary according to pathway. If anaxon in a 1:1 pathway dies, for example, the unsupportedoligodendrocyte will also die, whereas the loss of a sin-gle axon in a 1:60 pathway might not destroy any oligo-dendrocytes since each would be supported by the other59 axons. Thus, many unanswered questions remain:How many axonal segments must an oligodendrocytelose before it dies? Does maintenance of myelination de-pend on neural activity? Does neural activity affect oligo-dendrocyte turnover? How does oligodendrocyte deathaffect neurons? How does injury alter the balance be-tween myelin maintenance and oligodendrocyte turn-over?

CONCEPTS OF GLIAL TURNOVER

There is considerable controversy over critical con-cepts in oligodendrocyte biology. Do oligodendrocytesturn over in the normal or injured CNS? Are the charac-teristics of remyelination always identifiable, or is re-myelination sometimes anatomically indistinguishablefrom normal myelination?

The most commonly held beliefs are that mature oligo-dendrocytes are added to the CNS and that identifiable,abnormal anatomical features are the hallmarks of re-myelination. While strong data support this view, most

remyelination studies have examined models of severeinjury and models that do not faithfully reproduce dis-ease conditions or aging (Ludwin, 1988). Moreover, ax-onal sprouting occurs throughout adulthood in the CNS,but abnormal myelin has not been detected on such ax-ons. Also, methods for inducing demyelination typicallyproduce substantial additional tissue injury.

Studies using radionucleotides and short survival in-tervals have suggested that oligodendrocyte turnoverdoes not occur, or occurs only to a limited degree, in themature CNS. However, examination after longer survivalperiods have suggested that new oligodendrocytes areborn and added slowly throughout life, with minimal lossover a 6-month period (Adrian and Walkker, 1962). Al-ternative interpretations of these data are defensible, however. Electron microscopy studies quantifying thenumber of neuroglia in the adult brain suggested that oligodendroglial populations remain fairly stable(Vaughan and Peters, 1974), that oligodendrocytes con-tinue to proliferate in the adult CNS (Skoff et al., 1976),and that a pronounced increase occurs in very old rats(Dalton et al., 1968) and following injury (Adrian andWalkker, 1962; Arenella and Herndon, 1984; Herndon etal., 1977). Generally, injury or cell death stimulates con-current birth.

Could the increased birthrate in senescent rats repre-sent failed maintenance of myelination or a delimited butlong life span for oligodendrocytes? In the spinal cord ofadult rats, oligodendrocyte proliferation predominates inwhite matter, and appears to involve mostly a precursorcell that can differentiate into oligodendrocytes, astro-cytes and possibly neurons. Such precursors reside inwhite matter rather than in the central canal (Horner etal., 2000, 2002). Furthermore, quantitative ultrastructuralstudies indicate that oligodendrocytes become moreabundant in cortical white matter as animals age (Sandelland Peters, 2002). In area 17 of adult monkeys, for ex-ample, the number increases by about 15% with advanc-ing age (Peters et al., 1991). Myelin degradation is alsovery common in the cortex of old monkeys, and it cor-relates well with decreased performance on cognitivetasks (Peters et al., 1994). It also parallels the addition ofnew oligodendrocytes, and likely reflects the known on-going low-level loss of oligodendrocytes in the adult CNS(Dalton et al., 1968; Mori and Leblond, 1970). Additionalstudies in the optic nerve of aged monkeys indicate thatthe number of oligodendrocytes actually increases whennerve fiber loss is moderate but begins to decline onceaxonal loss in the nerve reaches a threshold value of900,000 (Sandell and Peters, 2002). These observationssuggest ongoing injury to myelin and/or oligodendro-cytes, and possible addition of new oligodendrocytes. Ir-radiation studies that are thought to deplete the CNS of

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progenitors have been interpreted to mean that oligoden-drocytes do not turn over, or at least turn over infre-quently (at intervals of years in rodents). This conclusionis based largely on the fact that progressive demyelina-tion is not observed. However, these studies examinedsurvival only over short periods (1–2 months) and did notdemonstrate that all sources of oligodendrocyte progen-itors were eliminated. Some evidence suggests that ma-ture oligodendrocytes have a defined lifespan, albeit verylong. First, ultrastructural studies have detected maturemyelinating oligodendrocytes with features of dying cells(Mori and Leblond, 1970). Second, 3H-thymidine labelsscattered mature oligodendroglia in the adult CNS, sug-gesting the need for new myelination (Dalton et al.,1968). Third, mature oligodendrocyte turnover time ap-pears to be 10–15 months in the rat (Imamoto et al.,1978), if assumptions about progenitor lifespan and la-beling indexes in the adult CNS are correct.

Additional information about oligodendrocyte turnoverand remyelination will be critical to understanding andtreating demyelinating disorders. If oligodendrocyteturnover is substantial, CNS injury is likely to occur intwo stages. First, there would be an initial rapid loss ofmyelin and some replacement by oligodendrocyte prog-enitors. In the second stage, myelin would be lost veryslowly due to an inability to maintain normal oligoden-drocyte turnover. During aging, a slow dismantling ofmyelinated intracortical axons would be predicted to pro-duce very slow but profound CNS dysfunction. If re-myelination could occur with normal ultrastructural fea-tures, it would be undetectable. With these scenarios,myelination remodeling by experience becomes as plau-sible as experience-dependent remodeling of neuronalsynapses.

Oligodendrocytes are highly peculiar in that theysend myelinating processes over a large area (300 ìm2),myelinate only 10–20% of the axons within this radius(instead of myelinating the closest axons), seldommyelinate two contiguous segments of a single axon,and myelinate 1–60 paranodal segments (Raine, 1984;Remahl and Hildebrand, 1990). These unique featuresare optimal for a cell that turns over and thus has to bereplaced because axons tolerate the loss of a singlemyelin segment (Koles and Rasminsky, 1972), and seg-ment-to-segment replacement by the same oligoden-drocyte is not required.

Oligodendrocyte lifespan and turnover likely varyfrom tract to tract in relationship to birth date and hencepattern of myelination. Factors, such as impaired neuralactivity, that are specific to certain diseases, are likelycontributors. Overall, initial CNS damage may be just thebeginning of the problem, with later slow dismantling be-ing the more profound result of injury. Thus, the early

phases of common neuron-centric diseases, such asAlzheimer’s disease, likely involve oligodendrocyte ab-normalities and loss, whereas neuronal damage and lossoccur later.

INJURY AND DISEASE

Demyelination (loss of myelin) and dysmyelination(abnormal myelination) are important contributors to be-havioral deficits associated with CNS disorders (Blight,1983; Bunge et al., 1961, 1993). Thus, oligodendrocyteinjury and death play substantial roles in thede(dys)myelination that follows traumatic and ischemicCNS injuries (Becker et al., 2003; Liu et al., 1997; Mc-Donald et al., 1998a,b). Remyelination associates withimproved axonal conduction, but the adult CNS has alimited capacity to spontaneously remyelinate (Blake-more and Franklin, 2000; Blakemore et al., 2000; Blightand Young, 1989; Gilson and Blakemore, 1993;Keirstead and Blakemore, 1999; Ludwin, 1988, 1994;Ludwin and Bakker, 1988; Peters et al., 1991; Smith etal., 1979), particularly in humans (Nait-Oumesmar et al.,2000).

Most research has focused on gross demyelinationrather than on the subtler but potentially more deleteri-ous dysmyelination, whose role was largely inferred un-til it became possible to make more direct measurements(Totoiu and Keirstead, 2005). Because myelination is im-portant for synchronizing signals that arrive at distant tar-gets (Lang and Rosenbluth, 2003) and therefore for mus-cle coordination, asynchronous signals may cause noisein coding signals, action tremor, and lack of coordination(Hore et al., 1991; Lang and Rosenbluth, 2003; Rosen-bluth et al., 1994).

Indirect data suggest that persistent demyelinationleads to further axonal loss (Grigoriadis et al., 2004).Therefore, an injury is simply the beginning of loss offunction. Initially, it leads to primary axonal injury anddeath of oligodendrocytes. A secondary wave of celldeath, paralleling Wallerian degeneration, follows at pro-gressive distances from the injury site, compromising ax-onal integrity. It is predicted that this repetitive processimpairs maintenance of the CNS, particularly of oligo-dendrocytes. Could improper maintenance of the CNS bea primary factor limiting restoration of spontaneous func-tion?

Abnormal myelination is worse than no myelinationbecause it adds noise to the system, and bad informationcan be misleading. Since myelination ensures that signalsare transmitted simultaneously among a series of axons,even if the axons have different lengths, dysmyelinationcan cause mistimed signals.


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RECOVERY AND REGENERATION

Remyelination can occur after injury, but the observ-able myelin produced following CNS pathologies is be-lieved to be abnormal, and is characterized by shorter in-ternode segments, thinner myelin sheaths, and deviationfrom the normal linear relationship between the diame-ter of an axon and sheath thickness (Blakemore, 1974;Bunge et al., 1961; Ludwin, 1988; Ludwin and Bakker,1988; Ludwin and Maitland, 1984). Therefore, the properaxon-myelin relationship is not restored. Inadequatemethods for observing normal myelin following CNSpathology or normal aging might be one reason we ob-serve only abnormal myelin, however. Another might bethat myelin forms after injury without the benefit of theneuronal signals (or the ability to receive such signals)that guide myelination during development. Thus, mis-communication between oligodendrocyte precursors andmature neurons might lead to dysmyelination.

The many potential sources of remyelinating oligo-dendrocytes in the adult CNS include mature myelinat-ing oligodendrocytes (Ludwin, 1988), dedifferentiatingand dividing mature myelinating oligodendrocytes(Arenella and Herndon, 1984; Ludwin and Bakker, 1988;Sturrock and McRae, 1980), bi- and tri-potential precur-sors that reside in the parenchyma (Becker et al., 2003;Horner et al., 2000), and subventricular/subependymal(spinal cord central canal) early precursors (Adrian andWalkker, 1962; Johansson et al., 1999a,b; Weiss et al.,1996). However, the bulk of the evidence suggests thatoligodendrocyte precursors residing in white matter ofthe spinal cord represent the largest potential source ofremyelinating oligodendrocytes (Horner et al., 2000).

Oligodendrocyte precursors must first be recruited toa demyelinated site, where they must proliferate. Theymust then differentiate into mature oligodendrocytes.This sequence allows remyelination to be tightly regu-lated. The recruitment stage is maintained by the growthfactors PDGF-A and FGF-2 (McKay et al., 1997;Woodruff and Franklin, 1999). The differentiation stageis initiated by a reduction in PDGF-A and FGF-2 ex-pression and increased expression of IGF-1, TGF-�1, andCXCL-1 (a chemokine produced by activated macro-phages that repels oligodendrocyte precursors) (McKayet al., 1997; Tsai et al., 2002; Woodruff and Franklin,1999). However, the details differ among the various an-imal models used to study remyelination. Strictly speak-ing, it remains open whether oligodendrocyte progenitormigration is the result of selective attraction signalingversus random migration with superimposed selectivesurvival/death signaling.

Mature oligodendrocytes can potentially remyelinateby several mechanisms: (1) by reaching out an additional

arm to ensheathe another internode, (2) by dividing asym-metrically to produce a new oligodendrocyte (akin toSchwann cell division), and (3) by dedifferentiating intoa replicating oligodendrocyte precursor (like most otherglial cells). The relative roles of these processes remainconjectural.

Complete remyelination will likely require replicationof development. Therefore, radial expansion followed bylateral migration of oligodendrocytes will be important.The highly organized structure of white matter—evenlyspaced interfascicular rows of oligodendrocytes inter-spersed with astrocytes—will be difficult to reproduce.The final number of mature myelinating oligodendro-cytes is determined by the proliferative rate of their prog-enitors, cell migration, and programmed cell death (Bau-mann and Pham-Dinh, 2001; Franklin and Hinks, 1999).Mitogens for oligodendrocyte progenitors include PDGF,bFGF, IGF-1, NT-3 (in the presence of insulin, and PDGFor BDNF), GGF, CNTF (in the presence of PDGF), andelectrical activity. Survival factors for maturing oligo-dendrocytes include PDGF, IGF-1, NT-3, GGF, CNTF,IL-6, LIF, and Notch-1 activation. Factors that inhibitproliferation and induce maturation include TGF-� (in-hibits PDGF’s mitogenic role) and non-NMDA agonists(inhibit progenitor proliferation). Thus, temporal orches-tration of such key molecules will be required for suc-cessful restoration (Baumann and Pham-Dinh, 2001;David and Lacroix, 2003; Horner and Gage, 2000).

PROMOTING REMYELINATION

Of the general strategies, illustrated in Figure 2, aimedat regenerating the CNS, remyelination appears to be oneof the most feasible. Spontaneous remyelination was firstobserved in 1961 by Bunge et al. (1961), but was in-complete. Extensive remyelination has not been demon-strated to date, despite the production of oligodendrocytescapable of generating myelin.

The most compelling approaches to normal remyeli-nation are (1) induction of endogenous oligodendrocytesprogenitors or mature oligodendrocytes, and (2) trans-plantation of myelin-producing cells. Induction of en-dogenous progenitors should not be a problem. In fact,such cells are present in chronic multiple sclerosis (MS)lesions (Wolswijk, 2000), but appear to be quiescent.Most of the evidence suggests that new oligodendrocytesare generated from resident progenitors in the injured re-gion. Long-distance migration, though possible, typicallydoes not occur in the chronic MS plaque. However, it isclear that even the adult CNS retains the potential to gen-erate oligodendrocyte progenitors with extensive myeli-nation capacity. New progenitor cells can be produced

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by the SVZ, and they can migrate and participate inmyelination after injury (Franklin and Blakemore, 1995,1997), though not under normal conditions or in chronicMS lesions. Identified signals in demyelinated areas thatattract progenitors include expression of PSA-NCAM(Oumesmar et al., 1995) and components of the inflam-matory cascade (Tourbah et al., 1997). However, grow-ing evidence suggests that demyelinated areas lack mi-togens or the ability to respond to them. An obstacle toprecursor migration to a demyelinated site is the loss ofimportant migratory signals or important proteases, suchas matrix metalloproteinases. Thus, much work needs to

be done before endogenous oligodendrocyte precursorscan be harnessed in the clinic. Combinatorial treatmentsfor a complex pathology such as spinal cord injury (Fig.2) involving growth factors, cytokines, chemokines, andother regulators of oligodendrocyte proliferation, migra-tion, maturation, and cell death will need to be evaluatedthrough more advanced timelapsed approaches includingin vivo molecular imaging before they can be used on pa-tients. Moreover, observed remyelination should be strin-gently correlated with functional parameters that includelocomotion, sensation, and the autonomic functions thatare generally underrepresented in most animal studies.


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FIG. 2. Common strategies toward regeneration of the damaged spinal cord. (1) Anti-excitotoxic and anti-apoptotic drugs wouldprevent the progression of secondary injury due to necrotic and apoptotic cell death. (2) To compensate for demyelination, chem-icals that prevent conduction block in demyelinated areas and agents that encourage surviving oligodendrocytes to remyelinate ax-ons would be provided; lost oligodendrocytes would be replenished. (3) To remove inhibition, agents that block the actions of nat-ural inhibitors of regeneration or drugs that downregulate expression of inhibitory proteins would be provided. (4) To promoteaxonal regeneration, growth factors that promote regeneration (sprouting) of new axons would be provided. (5) To direct axons toproper targets, guidance molecules would be provided or their expression would be increased in host cells. (6) To provide bridges,bridges would be implanted into the cyst to provide directional scaffolding that encourages axon growth. (7) To replace lost cells,cells capable of generating of all cell types (progenitor cells or embryonic stem cells) would be implanted; substances that induceundifferentiated cells to replace dead cells would be provided. Also, transplanted cells would be used to deliver regenerative mol-ecules. (8) Not shown. Strategies to preserve reinnervation of the neuromuscular junction at the peripheral nerve level would beaddressed with administration of neural-induced stem cells capable of providing trophic support to denervated muscle. Also, dam-aged nerve roots would be constructed with peripheral nerve transfers and grafts to minimize morbidity due to secondary periph-eral nerve injury. (Reproduced with permission of Alexander and Turner Studio, FL,©2002 Edmond Alexander.)

Myelin-producing cells that are candidates for trans-plantation (as assessed on CNS demyelination modelsand injury models) include Schwann cells (Tuszynski etal., 1998), olfactory ensheathing glia (Santos-Benito andRamon-Cueto, 2003), stem cells derived from bone mar-row (Koshizuka et al., 2004), fetal or adult oligoden-droglial progenitors (Blakemore et al., 2000; Smith andBlakemore, 2000), adult neuronal progenitors (Kocsis etal., 2004), and embryonic stem cells (Liu et al., 2000;McDonald et al., 1999; Nistor et al., 2005). In additionto replacing lost cells, transplantation appears to modifythe host environment to promote endogenous remyelina-tion. In humans, therefore, the injury site might need tobe primed to optimize the ability of transplanted cells toinduce proper remyelination. Moreover, all of the cellsmentioned above differ in their ability to remyelinateCNS axons and in their susceptibility to graft rejection,potential to form tumors and teratomas, ability to mod-ify injury sites, and capacity for promoting functional re-covery. Our laboratory has utilized embryonic stem (ES)cells in an effort to promote remyelination, with promis-ing results (Fig. 3). However, a study that directly com-pares these parameters in one injury or disease model isurgently needed.

The role of myelin-associated molecules that activelyinhibit axonal regeneration is an important controversyin the field. These molecules include the membrane-bound protein Nogo-A, which is highly enriched in mam-malian CNS myelin and oligodendrocytes, myelin-asso-ciated glycoprotein (MAG), and oligodendrocyte-myelinglycoprotein precursor (OMgp). When one of these lig-ands binds to the Nogo-receptor (NgR) and NgR associ-ates with its co-receptor, a signaling pathway activatesand inhibits various downstream GTPases, thereby reg-ulating the actin cytoskeleton on axonal growth cones andinhibiting axonal growth (Sandvig et al., 2004). Whetherthese inhibitory proteins are uncovered by dysmyelina-tion or expressed in a functional state by immature oligo-dendrocytes is unclear. It does appear evident that dam-aged myelin specifically leads to functional expressionof the inhibitory activity. An important feature is that ax-onal regeneration is a balancing act of additive promo-tory and inhibitory signals. The relative importance of in-hibitors associated with myelin versus those associatedwith scar tissue is an active argument. It is likely that theprofound inhibition produced by astrocyte- and fibro-blast-associated inhibitors, such as CSGP, ephrins, phos-phocan, and others, at the scar interface is an early im-portant obstacle and that myelin-associated inhibitorsplay a more central role once axons have penetrated thescar barrier. Neutralization of individual inhibitors hasled to small but important functional regeneration; there-

fore, a more detailed combinatorial study is required toelucidate the roles of these molecules in regeneration.

USE IT OR LOSE IT

Most complications associated with neurological dis-ease result from the limited mobility that accompaniesparalysis, altered sensation, impaired coordination, andbalance (Fig. 4). Developmental data suggest that manyaspects of cellular regeneration are activity-dependentand that disruption of such activity can impair sponta-neous regeneration, particularly maintenance. For exam-ple, we know that the proliferation and differentiation ofoligodendrocyte progenitors, the maturation of oligoden-drocytes, and myelination are highly activity-dependent.Thus, disruption of activity during normal developmentcan severely impair myelination. The role of activity isalso likely to be critical for maintaining myelination.Such concepts may be especially true in spinal cord in-jury, which reduces activity in neural circuits below theinjury level (because of limited descending input acrossthe lesion) and blocks most sensory input from the limbs.Perhaps the promising early results of remyelination pro-motion are even more encouraging, given that the inter-ventions were performed when so many factors, includ-ing neural activity and physical integrity of the body,were not optimized.

THE HUMAN EXPERIENCE

Our understanding of oligodendrocyte biology in hu-mans is limited and largely inferred from vertebratestudies and immortalized human cell lines. More re-cently, studies of cultured oligodendrocyte progenitorsderived from fetuses postmortem or by biopsy fromadults have offered more insights. Human embryonicstem cells now offer a powerful tool for studying thephysiology and biology of normal human oligoden-droglia—wider availability of such cells could revolu-tionize neurobiology. To date, most of our understand-ing of disease states and responses to disease comesfrom animal models or—to a more limited extent—frompostmortem analysis of lesions. However, molecularmagnetic resonance imaging (MRI) technology is be-ginning to alter our insights into human disease and willsoon become an important tool in the armamentariumof the clinician-scientist.

Only a handful of early phase clinical trials (Table 2)have studied the feasibility of remyelinating axons in hu-mans (Reier, 2004). For definitive testing, it will be nec-

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FIG. 3. Embryonic stem (ES) cells differentiate into the principle types of neural cells, and produce mature oligodendrocyteswith normal anatomical features of axonal myelination and physiological response to neurotransmitters. Panel 1: Type I (A) andType II (B) astrocytes (anti-GFAP). (C) Oligodendrocytes (anti-O1). (D) Neurons (anti-�-tubulin). Scale bar � 10 �m. (Repro-duced with permission of Becker et al. 2003.) Panel 2: (A) O1 immunoreactivity (green) is superimposed on a phase-contrastimage in a mixed ES cell-derived neuronal/glial culture (white arrows indicate axons, and red arrows indicate O1 immunoreac-tive wrapped axonal segments). (B) Transmission electron microscopy (EM) shows myelin profiles typical of early myelination.(C) Electrophysiological responses of ES-derived oligodendrocytes to the listed neurotransmitters. (Reproduced with permissionfrom Liu et al., 2000.)

essary to produce remyelination, identify the level of re-myelination and correlate this with functional recovery;then temporarily remove the myelination and show thatremoval deletes the recovered function, and once againrestore function upon remyelination. A challenging busi-ness!

NOVEL APPROACHES FOR MEASURINGREMYELINATION

Before this definitive experiment can be performed, itwill be necessary to develop tools for quantitatively as-sessing the extent of myelination and remyelination. Dys-

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TABLE 2. TRIALS TO ASSESS THE SAFETY OF NEUROTRANSPLANTATION

Purpose Cellular source Outcome Centers

Human fetal Safe Gainsville, FLspinal cord(embryonic weeks6–9; average 7.5 wksgestational age)

Oligodendrocyte Safe Diacrin Study; Washington University, progenitors from St. Louis, MO, and Albany, NY;porcine fetal �www.diacrin.com/products.htm�spinal cord

Autologous In progress Proneuron Biotechnologies, Israel;activated �www.proneuron.com/index2.html�macrophages

Autologous In progress Madrid, Spainperipheral OEGand Schwanncells

Autologous In progress Brisbane, Australiacentral OEG cells

SCI, spinal cord injury; OEG, olfactory ensheathing glia.Reproduced from McDonald and Becker (2003).

Examine safety ofhuman fetalspinal cordtransplantationin chronic SCIwith progressivesyringomyelia

Examine safety of stem celltransplantationin chronictraumatic SCI

Examine safety of macrophagetransplantationin acute SCI(days 0–14)

Examine safety of OEGtransplantationin chronic SCI

Examine safety of OEGtransplantationin chronic SCI

FIG. 4. Optimal neural activity is required to maximize spontaneousrecovery of function after nervous system injury. Data from normal de-velopment of the nervous system demonstrate that too little or too muchneural activity disrupts important processes of development, includingthose expected to occur with regeneration such as cell birth, cell survival,fate/phenotype choices, migration, axonal elongation, guidance and pathfinding, synapse elimination, and myelination. The graph demonstratesthe hypothesized level of regeneration with increasing activity. Increasedneural activity in the cord (e.g., mediated by FES) will likely increaseregeneration. Decreased neural activity (e.g., mediated by Baclofen) in the spinal cord may decrease regeneration. The curve is bell-shaped,reflecting the idea that excessive activity might be deleterious to regen-eration. (Reproduced with permission from McDonald and Becker,2003.)

myelinating mutants are the simplest models to study, butwell-defined injury models and the more clinically rele-vant contusion injury models do not permit myelinationto be assessed easily.

The field also lacks imaging techniques that can visu-alize events involving molecules with radii in the rangeof 10�10 m and nanomolar to femtomolar functional con-centrations. However, noninvasive technologies such asMRI, magnetic resonance spectroscopy (MRS), andpositron emission tomography (PET) offer resolution inthe order of 10�3 to 10�9 m. Before these techniques canbe used to monitor myelination and remyelination in clin-ical and laboratory settings, we must design sensitiveprobes that allow high-resolution images to be acquiredat high speed, provide high specificity, high affinity, andconsiderable amplification, and are capable of overcom-ing the blood-brain barrier and cellular membranes (Artemov, 2003; Dzik-Jurasz, 2003).

Emerging MRI techniques offer unique opportunitiesfor indexing remyelination in humans. For example, mag-netic transfer (MT) and diffusion tensor imaging (DTI)provide complementary approaches for quantifying whitematter tracts. Recent studies indicate that MT can iden-tify white matter lesions with sensitivity far beyond thatof traditional MRI; this has allowed correlation of func-tion, physiology, and anatomy for the first time. DTI offers a view of axons grouping in white matter, and distinguishes among pathways. Molecular imaging isemerging as a premier technology at the subcellular leveland for tracking axonal pathways (Artemov, 2003; Dzik-Jurasz, 2003; Wakana et al., 2004). It should soon be pos-sible to obtain fMRI images of the interior of the spinalcord to gain novel insights into the pathophysiology ofSCI. Information about tract-specific function, the loca-tions of lesions and remyelinated regions, and studies thatcorrelate remyelination with return of function should al-low us to design clinical trials with the necessary nega-tive and positive internal controls.

CONCLUSION

New information always engenders more questionsthan answers. Some important remaining questions in thefield of myelination are: What regulates myelination?What decides which axonal segments a single oligoden-drocyte myelinates? Does single oligodendrocyte myeli-nate axons that have convergent or divergent activity?What factors are important for maintaining myelination?What limits endogenous remyelination? After an oligo-dendrocyte myelinates, say, 10 segments, how manybranches can it lose before it dies? Does death of an oligo-dendrocyte signal birth and replacement? Why does an

oligodendrocyte wrap an axonal segment so many timeswhen modeling indicates that as few as three wraps suf-fice for function? Which signals tell an oligodendrocyteto regulate so closely the total area of its surface mem-brane? What is the expected electrophysiological corre-late of remyelination?

Our concepts of neurological disease are more likelyto involve oligodendrocyte biology than currentlythought. The future will produce exciting informationabout these cells’ roles in myelination. Transplantation,though limited in its ability to provide widely availabletreatment, will help us understand the molecular eventsthat are important for remyelination. The ultimate goalwill be to take advantage of the resident endogenousoligodendrocyte progenitors that are normally born atsurprisingly high rates. It is predicted that knowledgeabout the factors that maintain myelination and supportnormal glial cell turnover will have an overriding influ-ence on our attempts to restore physical function.

REFERENCES

ADRIAN, E., and WALKKER, B. (1962). Incorporation ofthymidine-H3 by cells in normal and injured mouse spinalcord. J. Neuropathol. Exp. Neurol. 21, 597–609.

ALTMAN, J. (1962). Autoradiographic study of degenerativeand regenerative proliferation of neuroglia cells with tritiatedthymidine. Exp. Neurol. 5, 302–318.

ALTMAN, J., and BAYER, S.A. (1984). The development ofthe rat spinal cord. Adv. Anat. Embryol. Cell. Biol. 85,1–164.

ARENELLA, L.S., and HERNDON, R.M. (1984). Matureoligodendrocytes. Division following experimental demyeli-nation in adult animals. Arch. Neurol. 41, 1162–1165.

ARTEMOV, D. (2003). Molecular magnetic resonance imag-ing with targeted contrast agents. J. Cell. Biochem. 90,518–524.

BARRES, B.A., and RAFF, M.C. (1993). Proliferation of oligo-dendrocyte precursor cells depends on electrical activity inaxons. Nature 361, 258–260.

BARRES, B.A., and RAFF, M.C. (1999). Axonal control ofoligodendrocyte development. J. Cell. Biol. 147, 1123–1128.

BAUMANN, N., and PHAM-DINH, D. (2001). Biology ofoligodendrocyte and myelin in the mammalian central ner-vous system. Physiol. Rev. 81, 871–927.

BECKER, D., SADOWSKY, C.L., and MCDONALD, J.W.(2003). Restoring function after spinal cord injury. Neurolo-gist 9, 1–15.

BLAKEMORE, W.F. (1974). Pattern of remyelination in theCNS. Nature 249, 577–578.


355

BLAKEMORE, W.F., and FRANKLIN, R.J. (2000). Trans-plantation options for therapeutic central nervous system re-myelination. Cell Transplant. 9, 289–294.

BLAKEMORE, W.F., GILSON, J.M., and CRANG, A.J.(2000). Transplanted glial cells migrate over a greater dis-tance and remyelinate demyelinated lesions more rapidlythan endogenous remyelinating cells. J. Neurosci. Res. 61,288–294.

BLIGHT, A.R. (1983). Cellular morphology of chronic spinalcord injury in the cat: analysis of myelinated axons by line-sampling. Neuroscience 10, 521–543.

BLIGHT, A.R., and YOUNG, W. (1989). Central axons in in-jured cat spinal cord recover electrophysiological functionfollowing remyelination by Schwann cells. J. Neurol. Sci. 91,15–34.

BONGARZONE, E.R. (2002). Induction of oligodendrocytefate during the formation of the vertebrate neural tube. Neu-rochem. Res. 27, 1361–1369.

BUNGE, R.P. (1968). Glial cells and the central myelin sheath.Physiol. Rev. 48, 197–251.

BUNGE, M.B., and PEARSE, D.D. (2003). Transplantationstrategies to promote repair of the injured spinal cord. J. Re-habil. Res. Dev. 40, 55–62.

BUNGE, R.P., BUNGE, M.B., and RISH. (1960). Electron mi-croscopic study of demyelination in an experimentally in-duced lesion in adult cat spinal cord. J. Biophys. Biochem.Cytol. 7, 685–696.

BUNGE, M.B., BUNGE, R.P., and RIS, H. (1961). Ultrastruc-tural study of remyelination in an experimental lesion in adultcat spinal cord. J. Biophys. Biochem. Cytol. 10, 67–94.

BUNGE, R.P., PUCKETT, W.R., BECERRA, J.L., MAR-CILLO, A., and QUENCER, R.M. (1993). Observations onthe pathology of human spinal cord injury. A review and clas-sification of 22 new cases with details from a case of chroniccord compression with extensive focal demyelination. Adv.Neurol. 59, 75–89.

CAJAL, S. (1909). Histology of the Nervous System. OxfordUniversity Press: New York.

DALTON, M.M., HOMMES, O.R., and LEBLOND, C.P.(1968). Correlation of glial proliferation with age in themouse brain. J. Comp. Neurol. 134, 397–400.

DAVID, S., and LACROIX, S. (2003). Molecular approachesto spinal cord repair. Annu. Rev. Neurosci. 26, 411–440.

DAWSON, M.R., LEVINE, J.M., and REYNOLDS, R.(2000). NG2-expressing cells in the central nervous sys-tem: are they oligodendroglial progenitors? J. Neurosci.Res. 61, 471–479.

DEMERENS, C., STANKOFF, B., LOGAK, M., et al. (1996).Induction of myelination in the central nervous system by elec-trical activity. Proc. Natl. Acad. Sci. USA 93, 9887–9892.

DOETSCH, F., GARCIA-VERDUGO, J.M., and ALVAREZ-BUYLLA, A. (1997). Cellular composition and three-dimensional organization of the subventricular germinalzone in the adult mammalian brain. J. Neurosci. 17,5046–5061.

DZIK-JURASZ, A.S. (2003). Molecular imaging in vivo: anintroduction. Br. J. Radiol. 76, S98–S109.

EHRENBERG, C. (1837). Observations on the structure hith-erto unknown of the nervous system in man and animals. Edinb. Med. Surg. J. 48, 257–305.

FRANKLIN, R.J., and BLAKEMORE, W.F. (1995). Glial-celltransplantation and plasticity in the O-2A lineage—implica-tions for CNS repair. Trends Neurosci. 18, 151–156.

FRANKLIN, R.J., and BLAKEMORE, W.F. (1997). Trans-planting oligodendrocyte progenitors into the adult CNS. J.Anat. 190, 23–33.

FRANKLIN, R.J., and HINKS, G.L. (1999). UnderstandingCNS remyelination: clues from developmental and regener-ation biology. J. Neurosci. Res. 58, 207–213.

GARCIA-VERDUGO, J.M., DOETSCH, F., WICHTERLE,H., LIM, D.A., and ALVAREZ-BUYLLA, A. (1998). Ar-chitecture and cell types of the adult subventricular zone: insearch of the stem cells. J. Neurobiol. 36, 234–248.

GEREN, B. (1954). The formation from the Schwann cell sur-face of myelin in the peripheral nerves of chick embryos.Exp. Cell Res. 7, 558–562.

GILSON, J., and BLAKEMORE, W.F. (1993). Failure of re-myelination in areas of demyelination produced in the spinalcord of old rats. Neuropathol. Appl. Neurobiol. 19, 173–181.

GLOVER, J.C. (2000). Development of specific connectivitybetween premotor neurons and motoneurons in the brain stemand spinal cord. Physiol. Rev. 80, 615–647.

GRIGORIADIS, N., BEN-HUR, T., KARUSSIS, D., andMILONAS, I. (2004). Axonal damage in multiple sclerosis:a complex issue in a complex disease. Clin. Neurol. Neuro-surg. 106, 211–217.

GUMPEL, M., BAUMANN, N., RAOUL, M., and JACQUE,C. (1983). Survival and differentiation of oligodendrocytesfrom neural tissue transplanted into newborn mouse brain.Neurosci. Lett. 37, 307–311.

HERNDON, R.M., PRICE, D.L., and WEINER, L.P. (1977).Regeneration of oligodendroglia during recovery from de-myelinating disease. Science 195, 693–694.

HORE, J., WILD, B., and DIENER, H.C. (1991). Cerebellardysmetria at the elbow, wrist, and fingers. J. Neurophysiol.65, 563–571.

HORNER, P.J., and GAGE, F.H. (2000). Regenerating the dam-aged central nervous system. Nature 407, 963–970.

HORNER, P.J., POWER, A.E., KEMPERMANN, G., et al.(2000). Proliferation and differentiation of progenitor cells

MCDONALD AND BELEGU

356

throughout the intact adult rat spinal cord. J. Neurosci. 20,2218–2228.

HORNER, P.J., THALLMAIR, M., and GAGE, F.H. (2002).Defining the NG2–expressing cell of the adult CNS. J. Neu-rocytol. 31, 469–480.

HUXLEY, A., and STAMPELL, R. (1949). Evidence for salta-tory conduction in peripheral myelinated nerve fibers. J.Physiol. (Lond.) 108, 315–339.

IMAMOTO, K., PATERSON, J.A., and LEBLOND, C.P.(1978). Radioautographic investigation of gliogenesis inthe corpus callosum of young rats. I. Sequential changesin oligodendrocytes. J. Comp. Neurol. 180, 115–128,132–137.

JOHANSSON, C.B., MOMMA, S., CLARKE, D.L., RISLING,M., LENDAHL, U., and FRISEN, J. (1999a). Identificationof a neural stem cell in the adult mammalian central nervoussystem. Cell 96, 25–34.

JOHANSSON, C.B., SVENSSON, M., WALLSTEDT, L.,JANSON, A.M., and FRISEN, J. (1999b). Neural stem cellsin the adult human brain. Exp. Cell. Res. 253, 733–736.

KEIRSTEAD, H.S., and BLAKEMORE, W.F. (1999). The roleof oligodendrocytes and oligodendrocyte progenitors in CNSremyelination. Adv. Exp. Med. Biol. 468, 183–197.

KOCSIS, J.D., AKIYAMA, Y., and RADTKE, C. (2004).Neural precursors as a cell source to repair the demyelinatedspinal cord. J. Neurotrauma 21, 441–449.

KOLES, Z.J., and RASMINSKY, M. (1972). A computer sim-ulation of conduction in demyelinated nerve fibres. J. Phys-iol. 227, 351–364.

KOSHIZUKA, S., OKADA, S., OKAWA, A., et al. (2004).Transplanted hematopoietic stem cells from bone marrowdifferentiate into neural lineage cells and promote functionalrecovery after spinal cord injury in mice. J. Neuropathol. Exp.Neurol. 63, 64–72.

LANG, E.J., and ROSENBLUTH, J. (2003). Role of myelina-tion in the development of a uniform olivocerebellar con-duction time. J. Neurophysiol. 89, 2259–2270.

LIN, S.C., and BERGLES, D.E. (2002). Physiological charac-teristics of NG2-expressing glial cells. J. Neurocytol. 31,537–549.

LIU, X.Z., XU, X.M., HU, R., et al. (1997). Neuronal and glialapoptosis after traumatic spinal cord injury. J. Neurosci. 17,5395–5406.

LIU, S., QU, Y., STEWART, T.J., et al. (2000). Embryonicstem cells differentiate into oligodendrocytes and myelinatein culture and after spinal cord transplantation. Proc. Natl.Acad. Sci. USA 97, 6126–6131.

LUBETZKI, C., DEMERENS, C., and ZALC, B. (1997). Sig-naux axonaux et myelinogenes dans le systeme nerveux cen-tral. Medecine/Sciences 13, 1097–1105.

LUDWIN, S.K. (1979). The perineuronal satellite oligoden-drocyte. A role in remyelination. Acta Neuropathol. (Berl.)47, 49–53.

LUDWIN, S.K. (1988). Remyelination in the central nervoussystem and the peripheral nervous system. Adv. Neurol. 47,215–254.

LUDWIN, S.K. (1994). Central nervous system remyelination:studies in chronically damaged tissue. Ann. Neurol. 36,S143–S145.

LUDWIN, S.K., and BAKKER, D.A. (1988). Can oligoden-drocytes attached to myelin proliferate? J. Neurosci. 8,1239–1244.

LUDWIN, S.K., and MAITLAND, M. (1984). Long-term re-myelination fails to reconstitute normal thickness of centralmyelin sheaths. J. Neurol. Sci. 64, 193–198.

MATURANA, H. (1960). The fine anatomy of the optic nerveof anurans—an EM study. J. Biophys. Biochem. Cytol. 7,107–120.

MCDONALD, J.W., and BECKER, D. (2003). Spinal cord in-jury: promising interventions and realistic goals. Am. J. Phys.Med. Rehabil. 82, S38–S49.

MCDONALD, J.W., ALTHOMSONS, S.P., HYRC, K.L.,CHOI, D.W., and GOLDBERG, M.P. (1998a). Oligoden-drocytes from forebrain are highly vulnerable toAMPA/kainate receptor-mediated excitotoxicity. Nat. Med.4, 291–297.

MCDONALD, J.W., LEVINE, J.M., and QU, Y. (1998). Mul-tiple classes of the oligodendrocyte lineage are highly vul-nerable to excitotoxicity. Neuroreport 9, 2757–2762.

MCDONALD, J.W., LIU, X.Z., QU, Y., et al. (1999). Trans-planted embryonic stem cells survive, differentiate and pro-mote recovery in injured rat spinal cord. Nat. Med. 5,1410–1412.

MCKAY, J.S., BLAKEMORE, W.F., and FRANKLIN, R.J.(1997). The effects of the growth factor-antagonist, trapidil,on remyelination in the CNS. Neuropathol. Appl. Neurobiol.23, 50–58.

MORI, S., and LEBLOND, C.P. (1970). Electron microscopicidentification of three classes of oligodendrocytes and a pre-liminary study of their proliferative activity in the corpus cal-losum of young rats. J. Comp. Neurol. 139, 1–28.

NAIT-OUMESMAR, B., LACHAPELLE, F., DECKER, L.,and BARON-VAN EVERCOOREN, A. (2000). Do centralnervous system axons remyelinate? Pathol. Biol. (Paris) 48,70–79.

NISTOR, G.I., TOTOIU, M.O., HAQUE, N., CARPENTER,M.K., and KEIRSTEAD, H.S. (2005). Human embryonicstem cells differentiate into oligodendrocytes in high purityand myelinate after spinal cord transplantation. Glia 49,385–396.


357

OUMESMAR, B.N., VIGNAIS, L., DUHAMEL-CLERIN, E.,AVELLANA-ADALID, V., ROUGON, G., and BARON-VAN EVERCOOREN, A. (1995). Expression of the highlypolysialylated neural cell adhesion molecule during postna-tal myelination and following chemically induced demyeli-nation of the adult mouse spinal cord. Eur. J. Neurosci. 7,480–491.

PENFIELD, W. (1932). Cytology and Cellular Pathology of theNervous System. Paul B. Hoeber: New York.

PETERS, A. (1960). The structure of myelin sheaths in the CNSof Xenopus laevis. J. Biophys. Biochem. Cytol. 7, 121–126.

PETERS, A., JOSEPHSON, K., and VINCENT, S.L. (1991).Effects of aging on the neuroglial cells and pericytes withinarea 17 of the rhesus monkey cerebral cortex. Anat. Rec. 229,384–398.

PETERS, A., LEAHU, D., MOSS, M.B., and MCNALLY, K.J.(1994). The effects of aging on area 46 of the frontal cortexof the rhesus monkey. Cereb. Cortex 4, 621–635.

RAINE, C.S. (1984). Biology of disease. Analysis of autoim-mune demyelination: its impact upon multiple sclerosis. Lab.Invest. 50, 608–635.

RANVIER, L.-A. (1871). Contributions a l’histologie et a laphysiologie des nerf periferiques. Comp. Rend. Acad. Sci.(Paris) 73, 1168–1171.

REIER, P.J. (2004). Cellular transplantation strategies for spinalcord injury and translational neurobiology. NeuroRx 1,424–451.

REMAHL, S., and HILDEBRAND, C. (1990). Relations be-tween axons and oligodendroglial cells during initialmyelination. II. The individual axon. J. Neurocytol. 19,883–898.

RIO HORTEGA, D. (1928). Tercera aportacion alconocimiento morfologico e intertretacion funcional de laoligodendroglia. Memor. Real. Soc. Esp. Hist. Nat. 14,5–122.

ROSENBLUTH, J., GUO, D., LIU, Z., LIANG, W.L., andSCHIFF, R. (1994). Effects of cerebellar lesions on tonicseizures, tremor and lifespan in myelin-deficient rats. BrainRes. 650, 85–92.

SANDELL, J.H., and PETERS, A. (2002). Effects of age onthe glial cells in the rhesus monkey optic nerve. J. Comp.Neurol. 445, 13–28.

SANDVIG, A., BERRY, M., BARRETT, L.B., BUTT, A.,and LOGAN, A. (2004). Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptorsignaling, and correlation with axon regeneration. Glia 46,225–251.

SANTOS-BENITO, F.F., and RAMON-CUETO, A. (2003).Olfactory ensheathing glia transplantation: a therapy to pro-mote repair in the mammalian central nervous system. Anat.Rec. B. New Anat. 271, 77–85.

SMITH, E.J., BLAKEMORE, W.F., and MCDONALD, W.I.(1979). Central remyelination restores secure conduction.Nature 280, 395–396.

SMITH, P.M., and BLAKEMORE, W.F. (2000). Porcine neuralprogenitors require commitment to the oligodendrocyte lin-eage prior to transplantation in order to achieve significantremyelination of demyelinated lesions in the adult CNS. Eur.J. Neurosci. 12, 2414–2424.

SKOFF, R.P., PRICE, D.L., and STOCKS, A. (1976). Electronmicroscopic autoradiographic studies of gliogenesis in rat op-tic nerve. II. Time of origin. J. Comp. Neurol. 169, 313–334.

STURROCK, R.R., and MCRAE, D.A. (1980). Mitotic divisionof oligodendrocytes which have begun myelination. J. Anat.131, 577–582.

TASAKI, I. (1939). The electro-saltatory transmission of thenerve impulse and the effect of narcosis upon the nerve fiber.Am. J. Physiol. 127, 211–227.

TOTOIU, M.O., and KEIRSTEAD, H.S. (2005). Spinal cordinjury is accompanied by chronic progressive demyelination.J. Comp. Neurol. 486, 373–383.

TOURBAH, A., LINNINGTON, C., BACHELIN, C., AVEL-LANA-ADALID, V., WEKERLE, H., and BARON-VAN EVERCOOREN, A. (1997). Inflammation promotessurvival and migration of the CG4 oligodendrocyte prog-enitors transplanted in the spinal cord of both inflamma-tory and demyelinated EAE rats. J. Neurosci. Res. 50,853–861.

TSAI, H.H., FROST, E., TO, V., et al. (2002). The chemokinereceptor CXCR2 controls positioning of oligodendrocyte pre-cursors in developing spinal cord by arresting their migra-tion. Cell 110, 373–383.

TUSZYNSKI, M.H., WEIDNER, N., MCCORMACK, M.,MILLER, I., POWELL, H., and CONNER, J. (1998). Graftsof genetically modified Schwann cells to the spinal cord: sur-vival, axon growth, and myelination. Cell Transplant. 7,187–196.

VAN DER KNAAP, M., and VALK, J. (1995). Myelinationand retarded myelination, in: Magnetic Resonance of Myelin,Myelination and Myelin Disorders. Springer: Berlin, pps.31–57.

VAUGHAN, D.W., and PETERS, A. (1974). Neuroglial cellsin the cerebral cortex of rats from young adulthood to oldage: an electron microscope study. J. Neurocytol. 3, 405–429.

VIRCHOW, R. (1846). Ueber das granulirte Aussehen derWandungen der Gehirnventrikel. Allg. Z. Psychiat. 3,242–250.

VIRCHOW, R. (1858). Cellular Pathology. Churchill: London.

WAKANA, S., JIANG, H., NAGAE-POETSCHER, L.M.,VAN ZIJL, P.C., and MORI, S. (2004). Fiber tract-basedatlas of human white matter anatomy. Radiology 230,77–87.

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358

WEISS, S., DUNNE, C., HEWSON, J., et al. (1996). Multipo-tent CNS stem cells are present in the adult mammalian spinalcord and ventricular neuroaxis. J. Neurosci. 16, 7599–7609.

WOLSWIJK, G. (2000). Oligodendrocyte survival, loss andbirth in lesions of chronic-stage multiple sclerosis. Brain 123,105–115.

WOODRUFF, R.H., and FRANKLIN, R.J. (1999). The ex-pression of myelin protein mRNAs during remyelination of lysolecithin-induced demyelination. Neuropathol. Appl.Neurobiol. 25, 226–235.

Address reprint requests to:Dr. John W. McDonald

International Center for Spinal Cord InjuryKennedy-Krieger Institute

Johns Hopkins University School of MedicineBaltimore, MD 21205

E-mail: [email protected]


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Demyelination and Remyelination after Spinal Cord Injury