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The Journal of Neuroscience, April 1, 2002, 22(7):2451-2459
The Age-Related Decrease in CNS Remyelination Efficiency Is
Attributable to an Impairment of Both Oligodendrocyte Progenitor
Recruitment and Differentiation
Fraser J.
Sim1, 2,
Chao
Zhao1,
Jacques
Penderis1, 3, and
Robin J. M.
Franklin1
1 Department of Clinical Veterinary Medicine,
University of Cambridge, Cambridge CB3 0ES, United Kingdom,
2 Department of Anatomy, University of Cambridge,
Cambridge, CB2 3DY, United Kingdom, 3 Animal Health Trust,
Kentford, Newmarket CB8 7UU, United Kingdom
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ABSTRACT |
The age-associated decrease in the efficiency of CNS remyelination
has clear implications for recovery from demyelinating diseases such as
multiple sclerosis (MS) that may last for several decades. Developing
strategies to reverse the age-associated decline requires the
identification of how the regenerative process is impaired. We
addressed whether remyelination becomes slower because of an impairment
of recruitment of oligodendrocyte progenitors (OPs) or, as is the case
in some MS lesions, an impairment of OP differentiation into
remyelinating oligodendrocytes. The OP response during remyelination of
focal, toxin-induced CNS demyelination in young and old rats was
compared by in situ hybridization using probes to two
OP-expressed mRNA species: platelet-derived growth factor- receptor
and the OP transcription factor myelin transcription factor 1 (MyT1). We found that the expression patterns for the two OP markers
are very similar and reveal a delay in the colonization of the
demyelinated focus with OPs in the old animals compared with the young
animals. By comparing the mRNA expression pattern of MyT1 with that of
the myelin proteins myelin basic protein and Gtx, we found that
in the old animals there is also a delay in OP differentiation that
increases with longer survival times. These results indicate that the
age-associated decrease in remyelination efficiency occurs because of
an impairment of OP recruitment and the subsequent differentiation of
the OPs into remyelinating oligodendrocytes, and that strategies
aimed at ameliorating the age-associated decline in remyelination
efficiency will therefore need to promote both components of the
regenerative process.
Key words:
aging; demyelination; remyelination; in
situ hybridization; oligodendrocyte progenitor; myelin
transcription factor 1; platelet-derived growth factor receptor
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INTRODUCTION |
Remyelination is a spontaneously
occurring repair process in which new myelin sheaths are restored to
demyelinated CNS axons (Franklin, 1999 ). Like many repair processes in
the body, it becomes less efficient with age (Gilson and Blakemore,
1993; Ashcroft et al., 1995; Shields et al., 1999; Musaro et al.,
2001). This decrease in efficiency manifests itself as a decrease in
the rate of remyelination (Shields et al., 1999; Sim et al., 2000) and is associated with changes in the inflammatory response and in the
expression of putative signaling molecules (Hinks and Franklin, 2000).
In addition to the evident implications of this phenomenon for
decreased likelihood of recovery from demyelinating diseases such as
multiple sclerosis with aging, the decrease in remyelination efficiency
also provides an opportunity to study the mechanisms of the process
itself. Thus, by comparing remyelination in young adults with
remyelination in older adults, one can identify those factors that must
be present or absent for the process to proceed efficiently and that
may form the basis for the development of therapies for promoting
endogenous remyelination.
Increasing evidence supports a cellular model of CNS remyelination that
involves (1) the recruitment of oligodendrocyte progenitors (OPs) into
areas of remyelination, a process that is likely to involve both their
migration and proliferation, and (2) their subsequent differentiation
into remyelinating oligodendrocytes (Godfraind et al., 1989; Reynolds
and Wilkin, 1993; Carroll and Jennings, 1994; Franklin et al., 1997;
Gensert and Goldman, 1997; Carroll et al., 1998; Redwine and Armstrong,
1998; Cenci di Bello et al., 1999; Levine and Reynolds, 1999). A delay
in the rate of remyelination could result from a decrease in the
recruitment of OPs, a decrease in the rate at which the recruited OPs
differentiate into remyelinating oligodendrocytes, or a combination of
the two. Determining which of these factors are contributing to the
delay in remyelination in old animals is important if one is to devise means of reversing the age-related decline in remyelination efficiency. For example, are recruitment factors or differentiation factors necessary to accelerate the rate of remyelination? To resolve this
issue, we compared the recruitment of OPs after toxin-induced demyelination in the caudal cerebellar peduncle in young and old adult
female rats and compared these recruitment rates with the appearance of
remyelinating oligodendrocytes. We monitored the OP response using two
OP markers: platelet-derived growth factor- receptor (PDGF-R)
mRNA (Pringle et al., 1992; Nishiyama et al., 1996; Redwine and
Armstrong, 1998) and mRNA for the OP-expressed transcription factor
myelin transcription factor 1 (MyT1) (Kim and Hudson, 1992;
Armstrong et al., 1995; Wrathall et al., 1998). Our data indicate that
there is a delay in OP recruitment during slow remyelination in old
animals compared with rapid remyelination in young animals. Moreover,
in old animals, OPs recruited early in the repair process
differentiate rapidly into remyelinating oligodendrocytes, whereas at
later stages there is a delay in their differentiation. These data
therefore indicate that ameliorating the age-associated decline in
remyelination efficiency may require manipulations that enhance both OP
recruitment and OP differentiation.
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MATERIALS AND METHODS |
Focal demyelination of the caudal cerebellar peduncle in
the adult rat. Female Sprague Dawley rats (young adults, 8-10
weeks of age, ~200 gm; old adults, ex-breeders, >12 months of age,
>280 gm) were used in all experiments. Experiments were performed in compliance with Home Office regulations and institutional guidelines. Anesthesia was induced using a neuroleptanalgesic combination [0.7
ml/kg Hypnorm (0.315 mg/ml fentanyl citrate and 10 mg/ml fluanisone;
Janssen Pharmaceuticals, Berse, Belgium) and diazepam (3 mg/kg; Phoenix
Pharmaceuticals, Gloucester, UK)]. Demyelination was induced
unilaterally or bilaterally by stereotaxic injection of 4 µl of
0.01% ethidium bromide (EB) into the caudal cerebellar peduncles as
described in detail previously (Woodruff and Franklin, 1999). Controls
were injected with an equal volume of sterile saline into the
contralateral peduncle of animals that received a unilateral lesion.
PDGF-R and Olig-1 in situ hybridization. The
PDGF-R probe was transcribed from a 1637 bp EcoRI cDNA
fragment encoding most of the extracellular domain of mouse PDGF-R
cloned into pBluescript KS+ (a gift from Dr. N. P. Pringle and
Prof. W. D. Richardson, University College London, London, UK).
The Olig-1 probe was transcribed from a 962 bp
SmaI-BamHI fragment of the Olig-1
3'-untranslated region cloned into pBluescript KSII (a gift from Dr.
R. H. Woodruff and Prof. W. D. Richardson, University College
London, with permission of Dr. D. H. Rowitch, Dana-Farber Cancer
Institute, Boston, MA). Groups of four animals were used for the
comparison of unlesioned numbers of PDGF-R and Olig-1 cells in the
caudal cerebellar peduncle. For the lesion study, groups of three to
six animals were perfused with 4% paraformaldehyde in PBS at 2, 5, 7, 10, 21, and 28 d after lesion induction in young and old adult
animals. Tissue was prepared for in situ hybridization
performed as described by Fruttiger et al. (1999), except that both the
RNA polymerases and the RNA transcription reactions were run as
recommended by Boehringer Mannheim Biochemica (Mannheim, Germany).
After in situ hybridization, RNA hybrids were visualized
in situ by a standard technique as described previously
(Fruttiger et al., 1999). The density of the PDGF-R- and
Olig-1-positive cells within the lesion was assessed by image analysis
(MCID model M4; Imaging Research Inc., Toronto, Canada).
EB-injected, saline-injected, or normal regions of the caudal
cerebellar peduncle, identified by solochrome cyanine staining, were
captured under the 4× objective using a red filter to accentuate the
blue-stained PDGF-R nuclei. The automatic target detection feature
of the MCID system was used to select positive nuclei, and the
threshold level was set according to the lesion background level such
that all positive nuclei were selected. The valid criteria for counting
a single cell were set as an area of >20
µm2. The average size of
PDGF-R-positive (+) cells was found to be ~60
µm2. Therefore, to allow estimation of
PDGF-R+ cells that appeared in "clumps," a target with an area
of >80 µm2 was counted as two or more
cells. However, to exclude areas of above-threshold nonspecific
staining such as section tears and folds, targets with an area of >200
µm2 were excluded. The MCID image
analysis system then calculated the cell density of positive cells.
MyT1 oligonucleotide probe synthesis and labeling. The MyT1
probe 5'-TTT GGG GCA AGC ATA CGT TTG CCA AAA ACC TGA GCA TCA AAA CTT
was designed to bind nucleotides 2151-2195 of mouse MyT1 mRNA following the numbering of Kim et al. (1997). MyT1 oligonucleotide probes were dissolved in sterile water to give a stock solution of 20 ng/µl and labeled as described previously (Hinks and Franklin, 1999).
Briefly, oligonucleotide probes were end-labeled with either 35S-dATP (1250 Ci/mmol; New England
Nuclear, Boston, MA) or [32P]dATP (6000 Ci/mmol; New England Nuclear) using terminal deoxynucleotidyl transferase and purified using Sephadex columns (Microbiospin 6;
Bio-Rad, Hemel Hempstead, UK) to remove free nucleotides. The radioactivity of the labeled probe was measured using a scintillation counter (1450 Microbeta; Wallac, Turku, Finland).
MyT1 northern blot analysis. Northern blot hybridization was
performed according to a standard protocol to confirm the size and
distribution of transcripts to which the MyT1
oligonucleotide probe bound (Hinks and Franklin, 1999). Briefly, total
RNA (20 µg) extracted from adult and neonatal rat tissues was
separated by 1% agarose-formaldehyde gel electrophoresis. The
separated RNA was transferred to a nitrocellulose membrane,
prehybridized, and then incubated at 42°C with hybridization buffer
containing [32P]dATP end-labeled
oligonucleotide probe at a final concentration of 3000 cpm/µl. After
hybridization, standard stringency washes were applied to remove
unbound probe, and washed membrane was apposed to autoradiographic film
(BioMax MS-1; Eastman Kodak Company, Rochester, NY) at  70°C
overnight. The transcript size was calculated by reference to standard
RNA markers.
MyT1 in situ hybridization. Groups of four to eight animals
were killed at 2, 5, 7, 10, 14, 21, 28, and 66 d after lesion induction. For MyT1 mRNA in situ hybridization, tissue was
prepared and in situ hybridization was performed as
described previously (Hinks and Franklin, 1999). Lesion-containing
sections of hindbrain were hybridized overnight in hybridization buffer
containing 3000 cpm/µl of
[35S]dATP-labeled oligonucleotide probe.
The following day, excess unbound and nonspecifically bound probe was
removed using standard stringency washes before exposure of sections to
autoradiographic film (BioMax MR; Eastman Kodak Company). The in
situ hybridization autoradiograms were analyzed using the MCID
image analysis system as described previously (Sim et al., 2000). In
addition, selected slides were coated with emulsion (LM1; Amersham
Biosciences, Arlington Heights, IL) and were developed and
counterstained with hematoxylin and eosin for microscopic examination
after 8 weeks in a light-proof box. The total number of
MyT1-positive cells was assessed by counting nuclei with
 20 silver grains. MyT1-positive nuclei were sampled across the entire
lesion area, which was identified as a hypercellular region compared
with the surrounding normal white matter that at the earlier time
points was found to be less eosinophilic than normal white matter. The
mean numbers of MyT1-positive cells were calculated for each animal.
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RESULTS |
EB injection creates a focal area of primary demyelination in which
PDGF-R, MyT1, and Olig-1 mRNA-expressing cells are undetectable
To compare the OP response with an acute episode of primary
demyelination in the young and old adult rat CNS, we used a model that
involves stereotaxic injection of EB into the caudal cerebellar peduncle, a sizable tract of large-diameter myelinated proprioceptive fibers en route from the spinal cord to the cerebellar cortex (Fig.
1). We have demonstrated previously that
this procedure results in rapid demyelination (Woodruff and Franklin,
1999) associated with the loss of myelin basic protein (MBP),
proteolipid protein (PLP), and Gtx mRNA-expressing
oligodendrocytes (Sim et al., 2000). The area of demyelination is
similar in young and old adult rats, and in both age groups, the lesion
eventually undergoes full remyelination, although at a slower rate in
the older age group (Shields et al., 1999; Sim et al., 2000). When,
fully remyelinated, the lesion has the same size in both young and old
animals. This indicates that the extent of demyelination and the small
degree of axonal loss are equivalent in the two age groups (Woodruff
and Franklin, 1999; Sim et al., 2000). There is also a loss of
astrocytes within the defined area of demyelination (Woodruff and
Franklin, 1999), and, on the basis of the probable mode of action of EB
as a DNA intercalating agent, implying a lack of cell specificity
(Neidle and Abraham, 1984), we postulated that there would also be an acute loss of OPs within this area. To test this possibility, we
examined expression of PDGF-R and MyT1 mRNAs, both of which are
specifically expressed by OPs in white matter (Pringle et al., 1992;
Armstrong et al., 1995) at 48 hr after EB injection. At this time, we
could detect no PDGF-R mRNA+ cells within a defined area that
corresponded to the area of demyelination detectable by solochrome
cyanine staining on adjacent sections in either young or old adult rats
(Fig. 2). This area also corresponded to
a region from which MyT1 mRNA expression was absent on autoradiography after in situ hybridization with
35S-labeled oligonucleotide probes (see
Fig. 6A). To provide additional evidence that OPs
were depleted from the area of demyelination, we also looked for
expression of Olig-1 mRNA, an oligodendrocyte lineage transcription
factor expressed immediately before PDGF-R mRNA during development,
but unlike PDGF-R, also expressed at subsequent stages of the
lineage (Lu et al., 2000; Zhou et al., 2000). Olig-1 mRNA-expressing
cells were also not detectable within the area of demyelination,
although they were abundant in the surrounding intact white matter
(Fig. 2). These data indicate that OPs as well as oligodendrocytes and
astrocytes are dramatically depleted by EB injection.
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Figure 1.
Toxin-induced CNS demyelinating lesion model. The
Nissl-stained coronal section illustrates lesion location in the
brainstem. Focal areas of demyelination were induced by stereotaxic
injection of EB into the caudal cerebellar peduncle of adult rats
(right, arrow). Modified from Swanson
(1998).
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Figure 2.
A, The caudal cerebellar peduncle
(ccp; indicated by the dashed
line) was identified histologically by solochrome
cyanine staining (left). Both PDGF-R+ OPs
(middle) and Olig-1+ oligodendrocyte lineage cells
(right) are found within the caudal cerebellar
peduncle. sp5, Spinal tract of the trigeminal.
B, After injection of EB, lesion location was identified
by solochrome cyanine staining (left). At 2 DPL, very
few OPs were identified within the lesion by in situ
hybridization for PDGF-R mRNA (middle). In addition,
all Olig-1-expressing oligodendrocyte lineage cells were depleted from
the lesion area (right). SC, Solochrome
cyanine. Scale bar, 500 µm.
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The caudal cerebellar peduncle contains similar numbers of
PDGF-R mRNA+ OPs in young and old adult rats
Given the depletion of cells expressing PDGF-R, MyT1, or Olig-1
mRNAs within the demyelinated area, the most likely source of the
majority of new oligodendrocytes required for remyelination is the OPs
that survive within the surrounding intact white matter. One
possibility for the decrease in remyelination efficiency with age is
that there is a corresponding decrease in the number of OPs available
to contribute to remyelination. To address this, we identified the
intact caudal cerebellar peduncle in unlesioned animals on solochrome
cyanine-stained sections and then counted the number of PDGF-R mRNA+
cells present within the tract in adjacent sections subjected to
in situ hybridization. We found that although there was a
decrease in the density of PDGF-R mRNA+ cells in old animals (Fig.
3B, control levels) associated
with a slight increase in the cross-sectional area of the tract, there was no significant difference in the total number of cells within the
caudal cerebellar peduncle in young and old adult rats (Figs. 2, 3).
This observation was supported by the similar relative optical
densities within the unlesioned caudal cerebellar peduncle in
autoradiographs after in situ hybridization with
35S-labeled MyT1-specific oligonucleotide
probes in the two age groups. It is therefore unlikely that the
differences in the availability of OPs contribute to the age-related
differences in remyelination rate.
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Figure 3.
A, Absolute numbers of PDGF-R+
OPs in the intact caudal cerebellar peduncles of young and old adult
rats, expressed as mean ± SEM. B, Quantification
of PDGF-R+ cell density expression during remyelination of
EB-induced demyelination of the caudal cerebellar peduncle. Changes in
mean density (± SEM) within the lesion between 2 and 28 DPL in young
and old animals are shown. The horizontal lines indicate the
mean OP density in young (solid line) and old (dotted
line) animals. *p < 0.05; significant
difference between young and old animals.
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The appearance of PDGF-R mRNA+ cells within areas of
demyelination indicates an age-related decline in the rate of OP
recruitment
We subsequently established whether differences existed in the
rate at which OPs accumulated within the demyelinated area in the two
age groups. This was initially addressed by measuring changes in the
density of PDGF-R mRNA+ cells at 2, 5, 7, 10, 21, and 28 d
after lesion induction [days postlesion (DPL)] (Fig. 3B).
Although virtually devoid of PDGF-R+ cells at 2 DPL, abundant positive cells were present at 5 DPL in young animals and 7 DPL in old
animals. At 5, 7, and 10 DPL, the density of PDGF-R+ cells in young
animals remained >200 cells/mm2 and at
all of these time points was significantly greater than the density in
old animals (p < 0.05). Although the density of PDGF-R+ cells in young animals remained greater than control levels
at 28 DPL, the densities had declined from peak levels. The old animal
showed a slow progressive increase in PDGF-R+ cell densities,
reaching densities similar to those in young animals by 21 DPL and
exceeding them at 28 DPL, when the density in young animals was in decline.
In old animals at 10 DPL, unlike the uniform distribution of PDGF-R+
cells in young animals, a significantly greater density of PDGF-R+
cells was found around the lesion edge than in the lesion core (Fig.
4). Thus, as a result of the slower
repopulation of the lesion by OPs in the old animals, it was possible
to observe an OP distribution that suggested that the lesion was
repopulated by OPs from the edge of the lesion inward.
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Figure 4.
In old animals 10 d after injection, the
spatial distribution of PDGF-R+ cells within the demyelinating
lesion was examined by image analysis (A).
Red- and green-labeled cells were counted
as cells present in the periphery and core of the lesion, respectively.
Cyan-colored areas of nonspecific staining were excluded
from analysis. The density of these cells and the ratio of peripheral
to core densities were calculated. Scale bar, 500 µm.
B, The box plot shows that the ratio is significantly
>1, indicating that more cells are present in the outer portion of the
lesion at 10 d.
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Changes in MyT1 mRNA expression pattern reflect changes in
PDGF-R mRNA expression during remyelination
To verify the age-related differences in OP recruitment, we
compared the PDGF-R mRNA response with that of another OP marker, the zinc finger transcription factor MyT1 (Kim and Hudson, 1992). This
involved the design of a new oligonucleotide probe specific for MyT1
mRNA. A total of 15 45-mer oligonucleotide probes were designed and
synthesized, and their binding specificity was tested by Northern blot
analysis on CNS tissues. The MyT1-5 probe was found to bind a single
mRNA species of ~5 kb (Fig. 5) and was therefore similar to the MyT1 transcript size previously determined by
Northern blot analysis (Kim and Hudson, 1992). In addition, the absence
of either a 7.5 kb or a 2.0 kb band indicated that the MyT1-5 probe
did not bind the closely related MyT1-like mRNA (Kim et al., 1997).
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Figure 5.
MyT1 Northern blot analysis. The MyT1-5 probe
binds to a single transcript of ~5 kb found in both developing CNS
and various adult tissues.
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The pattern of MyT1 mRNA expression during remyelination was analyzed
by measuring the optical density of the autoradiogram within the lesion
area relative to background level of expression. This relative optical
density (ROD) indicated the mean optical density across the entire
lesion area. When plotted against survival time, the MyT1 mRNA RODs
exhibited a biphasic pattern, with a sharp drop in density of
expression occurring between days 5 and 10 (Fig.
6). Although the first peak of MyT1 mRNA
expression coincided in young and old animals, the level of expression
in young animals was >40% higher than in old animals (Fig.
6B). In addition, there were age-related differences
in the second phase of MyT1 mRNA expression. MyT1 mRNA expression
increased more slowly and peaked ~2 weeks later in old animals. The
level of expression then declined to that of control in young animals
but remained significantly elevated in old animals at 66 DPL, at which
time remyelination is complete (Shields et al., 1999). This last
observation may be accounted for by the prolonged expression of OP
survival factors, such as insulin-like growth factor (IGF)-I, after
toxin-induced demyelination in old animals compared with young,
allowing the tissue to support a greater number of OPs (Hinks and
Franklin, 2000). Small ROD changes in young and old animals after
saline injection were not statistically significant (Fig.
6B, control groups).
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Figure 6.
A, Expression patterns of MyT1 mRNA
during remyelination of EB-induced demyelination of the caudal
cerebellar peduncle in both young and old adult animals. Sections
through the center of the lesion were hybridized with
35S-labeled MyT1-specific oligonucleotide probes using a
standard in situ hybridization protocol. Representative
autoradiograms demonstrate the resulting hybridization signal at 2, 5, 7, 10, 14, 21, 28, and 66 d after injection. Arrows
indicate the first time point at which the initial and second phases of
MyT1 re-expression were detected. Emulsion autoradiography of the
cerebellar cortex revealed that the signal in this region was diffuse
and not associated with individual cells, suggesting that it is caused
by nonspecific binding. Scale bar, 500 µm. B, Changes
in mean ROD measurements (± SEM) for MyT1 mRNA expression within
EB-induced lesions between 2 and 66 d after lesion induction in
young and old adult animals.
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We subsequently showed that the increased MyT1 ROD values reflected a
change in the density of cells expressing MyT1 mRNA. A comparison of
the total number of MyT1+ nuclei within the lesion with the equivalent
total ROD measurement (ROD × lesion area) revealed a close
correlation (p < 0.0001) and indicated that
after linear regression analysis, all points fit within the 95%
prediction interval (Fig. 7). The large
number of apparently overlapping grains and difficulties in the
identification of cellular boundaries in areas of densely packed MyT1+
cells made it difficult to investigate the amount of MyT1 mRNA
expressed per cell. However, because the relationship between MyT1+
cell density and ROD was so strong, it is unlikely that large changes
in level of expression per cell occurred.
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Figure 7.
A, The number of MyT1
mRNA-expressing cells during remyelination was assessed by emulsion
autoradiography. MyT1-positive nuclei were defined as nuclei containing
>20 silver grains clustered over a single nucleus. The field
illustrated is taken from an EB-induced lesion and contains five
MyT1-positive nuclei (arrows). Scale bar, 5 µm.
B, The changes in MyT1 ROD observed were compared with
changes in the absolute number of MyT1-positive nuclei by correlating
the total number of cells with the ROD × lesion area for each
animal. These data are significantly correlated with one another. In
addition, after linear regression (solid line), all data
points fall within the 95% prediction intervals (dashed
line). The data indicate that the ROD measurements (Fig.
6B) reflect changes in the density of MyT1
mRNA-expressing cells.
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The MyT1 expression pattern was then compared with the PDGF-R+ cell
density (Fig. 8). Although at early time
points the two patterns were different, in both young and old animals
the patterns of expression of the two markers after 10 DPL were
strikingly similar within an age group. This observation indicates that
changes in MyT1 ROD, at least from day 10 onward, not only reflect
changes in MyT1+ cell density but also changes in the density of
PDGF-R+ OPs.
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Figure 8.
Comparison of mRNA expression patterns of the OP
markers PDGF-R and MyT1 during remyelination of the caudal
cerebellar peduncle in young and old animals. Mean relative expression
values, relative to peak levels, were calculated for the two markers to
compare the two expression patterns. The shape of the mRNA profiles
after 10 DPL of MyT1 and PDGF-R was similar in both young
(A) and old (B)
groups.
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The latency between equivalent expression of an OP marker, MyT1,
and markers of myelinating oligodendrocytes MBP and Gtx increases in
old adult animals but remains relatively low and constant in young
animals
To examine the rate of differentiation of OPs into remyelinating
oligodendrocytes, the mRNA expression profile of the OP marker MyT1 was
compared with that of two markers of mature oligodendrocytes, MBP and
Gtx. We have shown previously that MBP and Gtx mRNAs have similar
patterns of expression during remyelination of EB-induced lesions in
the caudal cerebellar peduncle regardless of the rate at which
remyelination is occurring (Sim et al., 2000). Their expression
profiles correspond to the appearance of myelin sheaths within the
toxin-induced lesions, peaking when remyelination is complete and
declining thereafter (Shields et al., 1999; Sim et al., 2000). The
pattern of MyT1 mRNA expression during remyelination was clearly
different from that of MBP or Gtx in both age groups. Increased MyT1
mRNA levels were found before detectable MBP and Gtx re-expression, and
peak expression during the second phase of MyT1 expression preceded MBP
and Gtx peak expression in both young and old animals (Fig.
9A,B).
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Figure 9.
The rate of oligodendrocyte differentiation was
examined by comparison of the mRNA expression patterns of MyT1 for OPs
and MBP and Gtx for mature oligodendrocytes during remyelination of the
caudal cerebellar peduncle in young (top) and old
(middle) animals. These patterns were compared by
calculating a percentage of the individual ROD values to the highest
ROD observed for each probe. MyT1 expression preceded MBP and PLP in
each age group. Bottom, The relative delay between
equivalent MBP or Gtx expression and MyT1 expression was calculated
from the relative expression charts (top,
middle). Unlike young animals, the delay between Gtx and
MyT1 in old animals progressively increased as the lesion matured
before complete remyelination.
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The rate at which recruited OPs differentiate into remyelinating
oligodendrocytes is likely to be an important determinant of the rate
of remyelination. To establish whether differences existed between
young and old lesions in the length of time taken by recruited OPs to
undergo differentiation, we estimated the interval between equivalent
ROD expression levels of markers for OPs and mature oligodendrocytes.
The interval between equivalent levels of MyT1 and MBP or Gtx mRNA
expression, when expressed as a percentage of their maximal levels, was
approximately constant in young animals during mRNA accumulation (Fig.
9A,C). In contrast, this interval progressively increases
during remyelination in old animals from 3 d to >5 weeks (Fig.
9B,C). Thus, the rates of accumulation of the OP marker MyT1
and the myelinating oligodendrocyte markers MBP and Gtx proceed in
parallel in the young animals but, although initially closer in the old
animals than the young, diverge in the older animals. This difference
between the two age groups suggests that the decreased rate of
differentiation of OPs into remyelinating oligodendrocytes in old
animals is an important component of the age-related decline in
remyelination efficiency.
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DISCUSSION |
A prerequisite for enhancing the efficiency of remyelination in
the aging CNS is recognizing those aspects of the process that are
primarily responsible, which then determine the corrective strategy
adopted. In this study, we examined whether the age-related decrease in
the rate of remyelination after toxin-induced demyelination is a result
of an impairment of recruitment of OPs or their differentiation into
remyelinating oligodendrocytes.
The OP response to demyelination was followed using two OP markers:
PDGF-R mRNA (Pringle et al., 1992) and the transcription factor MyT1, which in postnatal white matter is expressed at highest levels in OPs (Armstrong et al., 1995; Nishiyama et al., 1996). At
early time points, the patterns of expression of MyT1 and PDGF-R were different, suggesting that immediately after
demyelination, the cellular origins of these two markers are not
identical. However, the similar expression patterns of the two markers
after 10 DPL and the fact that increased expression occurred solely in
white matter support the contention that the MyT1 mRNA expression
profiles reflected changes in OPs.
OPs are recruited into the lesions at a slower rate in the older
animals. Because neither of the OP markers was detectable within the
lesion at 2 DPL, it would appear that EB kills OPs as well as
oligodendrocytes and astrocytes (Woodruff and Franklin, 1999). The
issue arises as to whether other progenitor types that expressed
neither PDGF-R nor MyT1 mRNAs but are nevertheless capable of giving
rise to remyelinating oligodendrocytes might survive EB injection. This
is especially germane given the heterogeneity of dividing progenitor
phenotypes in the adult CNS (Gensert and Goldman, 2001) and the
contribution these cells make to the remyelinating oligodendrocyte
population (Gensert and Goldman, 1997; Keirstead and Blakemore, 1997).
We therefore examined the expression of another marker, the basic
helix-loop-helix transcription factor Olig-1, whose expression
in white matter is confined to the oligodendrocyte lineage (Lu et al.,
2000; Zhou et al., 2000). Olig-1 is expressed with a pattern that
during development precedes and overlaps that of PDGF-R, and it is
therefore likely to detect a spectrum of progenitor phenotypes
contributing to the genesis of remyelinating oligodendrocytes (Lu et
al., 2000). The absence of Olig-1 mRNA-expressing cells after EB
injection provided additional support for a focal depletion of
progenitor cells capable of contributing to remyelination. The
mechanism by which EB causes cell death is likely to relate to its
nucleic acid intercalating properties, disrupting protein synthesis
because of its effects on RNA and inhibiting mitochondrial RNA;
therefore, it is unlikely to be cell specific (Neidle and Abraham,
1984). Thus, although we cannot exclude the possibility that very small
numbers of OPs or indeed other progenitors that we were unable to
detect survived within the demyelinated area, the most likely source of
these cells is from outside the lesion. OP recruitment into the lesions
probably involves a combination of short-distance migration of
proliferating OPs from intact tissue into the lesion (Franklin et al.,
1997) and their proliferation within the lesion (Keirstead et al.,
1998; Levine and Reynolds, 1999). In old animals at 10 DPL, the density
of OPs was greater around the rim of the lesion than at its center, a
distribution consistent with the view that the lesion is repopulated
with OPs from outside in. This study and others indicate that the
process of OP recruitment is initiated shortly after lesion (Carroll
and Jennings, 1994; Keirstead et al., 1998; Levine and Reynolds, 1999; Nait-Oumesmar et al., 1999). We find no difference in the number of
PDGF-R+ cells or in the constitutive levels of MyT1 expression in
the normal cerebellar peduncles of young and old rats, suggesting that
the impairment of recruitment is not attributable to a deficiency in OP
availability but rather to an impairment of the factors involved in
their recruitment or a change in their intrinsic ability to respond to
these factors.
Currently, little is known about the factors that signal OP recruitment
after demyelination, although increased expression of factors known to
stimulate OP proliferation and motility have been described during
remyelination. For example, PDGF and fibroblast growth factor-2, both
of which promote proliferation and motility of adult OPs (Wolswijk et
al., 1991; Wolswijk and Noble, 1992), have increased levels of
expression triggered by demyelination and are associated with the early
stages of remyelination (Redwine and Armstrong, 1998; Hinks and
Franklin, 1999). A delay in the onset of increased PDGF-A mRNA
expression occurs after induction of lysolecithin-induced demyelination
in the spinal cord of old adult rats compared with young adult rats
(Hinks and Franklin, 2000). However, after the initial delay in the
onset of expression, similar levels are achieved in the two age groups.
If the PDGF response governed the behavior of OPs, then one would
predict that the start of recruitment would be delayed in old animals but thereafter would proceed at a rate similar to that in young animals. Instead, we found that the start of recruitment is similar but
the rate is different, suggesting that differences in the expression of
PDGF are not primarily responsible for the difference in recruitment
rate in the present study.
Having established that OP recruitment is delayed in slow remyelination
in old animals, we then addressed whether the differentiation phase of
remyelination was also altered by measuring the latency between
equivalent OP MyT1 mRNA expression and the expression of MBP and Gtx
mRNAs (Sim et al., 2000). In young animals, the latency remained
constant at 10 DPL, interpreted as a steady differentiation of
recruited cells into remyelinating oligodendrocytes until remyelination is complete. In contrast, in old animals, the latency increased as the
lesion aged and reached considerably higher levels than were found in
the young animals at 21 and 28 DPL. Because the onset of MBP and Gtx
mRNA expression occurred later in old animals, the first survival time
at which the analysis could be undertaken was 3 d later than in
young animals. At 3 DPL, the latency was shorter, suggesting that
remyelination was occurring more efficiently in the older age group.
However, this may simply have been a reflection of the delay in the
remyelination process and the fact that a similarly short interval
occurred in the young animals between 5 and 7 d. This difference
between the two age groups thus suggested that remyelination occurs
most efficiently when closely linked to the process of demyelination. A
likely explanation for the temporal association between demyelination
and remyelination is that the inflammatory response associated with
demyelination provides a powerful impetus for remyelination (Triarhou
and Herndon, 1985; Hiremath et al., 1998; Cenci di Bello et al, 1999;
Morell et al., 2000; Kotter et al., 2001; Mason et al., 2001). If the
remyelination process is still in progress as the
demyelination-associated inflammatory response subsides, then the
process loses momentum. In a lesion environment such as that induced by
EB, in which OPs repopulate the lesion from the outside inward, the
larger the lesion the longer it will take to become fully repopulated.
The situation we describe in the aged rat, in which differentiation of
recruited OPs becomes increasingly delayed, will be exacerbated in
large MS lesions, potentially leading to a cessation of OP
differentiation. Evidence that such a situation may arise comes from
the observation that some demyelinated MS lesions are replete with OPs
(Wolswijk, 1998; Chang et al., 2000). One possibility for
differentiation delay is the presence of inhibitory factors, and in
this regard, the axon with which a remyelinating OP must engage would
be a possible source of such factors. For example, differences between young and old animals in axonal expression of notch ligands such as
jagged may inhibit OP differentiation via activation of notch receptors
(Wang et al., 1998). Alternatively, differentiation-inducing signals
may be absent. Again, the demyelinated axons may play a role, with
those of the aged CNS being less receptive to remyelination than those
in younger animals. In the context of age-related changes in the
remyelinating environment, there is a delay in the peak expression of
IGF-I and transforming growth factor- 1 in old animals. Based on
their effects on oligodendrocyte lineage cells in vitro, these two growth factors have been proposed as putative inducers of OP
differentiation during remyelination (Hinks and Franklin, 2000). If
IGF-I and transforming growth factor-1 were inducing OP
differentiation, then the delay in their peak expression in old animals
after toxin-induced demyelination would be consistent with our present
observation on delayed differentiation in animals of similar ages.
An important implication of our results is that if efficient
remyelination is to be maintained throughout a protracted demyelinating disease such as MS, then strategies will have to be devised that promote both OP recruitment and OP differentiation. Single factors can
induce both proliferation and differentiation, depending on the length
of exposure (Rosenthal and Cheng, 1995). Few such factors are known for
the oligodendrocyte lineage, although a case can be made for IGF-I
having effects on both OP proliferation and differentiation (Ye et al.,
1995; Jiang et al., 2001). Nevertheless, it seems likely that
therapeutic strategies aimed at reversing age-related deficiencies in
remyelination will need to contain multiple components and be delivered
with a specific sequence and timing.
| |
FOOTNOTES |
Received Oct. 12, 2001; revised Jan. 4, 2002; accepted Jan. 8, 2002.
This work was supported by the Medical Research Council of Great
Britain and Northern Ireland, The Wellcome Trust, and Research into
Ageing. We thank Dr. Rachel Woodruff for her help with this study.
Correspondence should be addressed to Dr. R. J. M. Franklin,
Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK. E-mail: rjf1000{at}cam.ac.uk.
| |
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Impaired remyelination and depletion of oligodendrocyte progenitors does not occur following repeated episodes of focal demyelination in the rat central nervous system
Brain,
June 1, 2003;
126(6):
1382 - 1391.
[Abstract]
[Full Text]
[PDF]
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S. Belachew, A. A. Aguirre, H. Wang, F. Vautier, X. Yuan, S. Anderson, M. Kirby, and V. Gallo
Cyclin-Dependent Kinase-2 Controls Oligodendrocyte Progenitor Cell Cycle Progression and Is Downregulated in Adult Oligodendrocyte Progenitors
J. Neurosci.,
October 1, 2002;
22(19):
8553 - 8562.
[Abstract]
[Full Text]
[PDF]
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D M Chari and W F Blakemore
New insights into remyelination failure in multiple sclerosis: implications for glial cell transplantation
Multiple Sclerosis,
August 1, 2002;
8(4):
271 - 277.
[Abstract]
[PDF]
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L. Jasmin and P. T. Ohara
Remyelination within the CNS: Do Schwann Cells Pave the Way for Oligodendrocytes?
Neuroscientist,
June 1, 2002;
8(3):
198 - 203.
[Abstract]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
