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The Journal of Neuroscience, August 1, 2000, 20(15):5703-5708
Insulin-Like Growth Factor-1 Inhibits Mature Oligodendrocyte
Apoptosis during Primary Demyelination
J. L.
Mason1,
P.
Ye2,
K.
Suzuki3,
A. J.
D'Ercole2, and
G. K.
Matsushima1, 4
1 Curriculum in Neurobiology and University of North
Carolina Neuroscience Center, Departments of
2 Pediatrics, 3 Pathology and Laboratory
Medicine, and 4 Microbiology and Immunology and Program in
Molecular Biology and Biotechnology, University of North Carolina,
Chapel Hill, North Carolina 27599
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ABSTRACT |
Metabolic insult results in apoptosis and depletion of mature
oligodendrocytes during demyelination. To examine the role of insulin-like growth factor-1 (IGF-1) during acute demyelination and remyelination in the adult CNS, we exposed transgenic mice that
continuously express IGF-1 (IGF-1 tg) to cuprizone
intoxication. Demyelination was observed within the corpus callosum in
both wild-type and IGF-1 tg mice 3 weeks after exposure
to cuprizone. Wild-type mice showed significant apoptotic mature
oligodendrocytes and a dramatic loss of these cells within the lesion
that resulted in near complete depletion and demyelination by week 5. In contrast, the demyelinated corpus callosum of the IGF-1
tg mice was near full recovery by week 5. This rapid recovery
was apparently caused by survival of the mature oligodendrocyte
population because apoptosis was negligible, and by week 4, the mature
oligodendrocyte population was completely restored. Furthermore,
despite demyelination in both wild-type and IGF-1 tg
mice, oligodendrocyte progenitors accumulated only in the absence of
mature oligodendrocytes and failed to accumulate if the mature
oligodendrocytes remained as demonstrated in the IGF-1
tg mice. These results suggest that IGF-1 may be important in
preventing the depletion of mature oligodendrocytes in
vivo and thus facilitates an early recovery from demyelination.
Key words:
insulin-like growth factor-1; oligodendrocytes; progenitors; myelin; demyelination; apoptosis; mice; transgenic
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INTRODUCTION |
The terminal fate of demyelinating
disorders is thought to be a consequence of oligodendrocyte and/or
axonal depletion (Compston, 1996 ). Previous studies suggest that
chronic demyelination results from the depletion of the mature
oligodendrocytes within a lesion (Johnson and Ludwin, 1981; Mason et
al., 2000) (for review, see Raine, 1997). This depletion of the mature
oligodendrocytes appears to be caused by the apoptotic death of these
cells (Pender et al., 1991; Taniike et al., 1999; Mason et al., 2000).
The inhibition of oligodendrocyte death during primary demyelination,
therefore, may be critical in preventing the progression of a
demyelinating disease to a chronic state.
Insulin-like growth factor 1 (IGF-1) has been shown to induce
myelination in vitro (Mozell and McMorris, 1991) and
in vivo (for review, see D'Ercole et al., 1996; Werther et
al., 1998) while also protecting mature oligodendrocytes from a
pathological insult. IGF-1 has been demonstrated to reduce lesion
severity and clinical deficits in experimental autoimmune
encephalomyelitis (EAE) (Yao et al., 1995, 1996). Furthermore, IGF-1
promotes the long-term survival of mature oligodendrocytes in culture
(Barres et al., 1993) and inhibits mature oligodendrocyte apoptosis
in vitro (Cho et al., 1997; Ye and D'Ercole, 1999).
However, it is not known whether IGF-1 can inhibit mature
oligodendrocyte apoptosis in vivo after a demyelinating insult.
In this study, we used a transgenic line of mice expressing high levels
of IGF-1 within the brain (IGF-1 tg mice) (Ye et al., 1995)
to investigate whether IGF-1 can protect mature oligodendrocytes from
apoptotic death during primary demyelination in vivo. During cuprizone intoxication, acute demyelination occurs within the CNS
(Hiremath et al., 1998) that features mature oligodendrocyte apoptosis
and subsequent depletion of mature oligodendrocytes from the corpus
callosum (Mason et al., 2000). Although acute demyelination was
observed in both cuprizone-treated wild-type and IGF-1 tg
mice, mature oligodendrocyte death was predominantly observed in the
wild-type mice and infrequently detected in the IGF-1 tg
mice. Furthermore, an early recovery from demyelination was observed in
IGF-1 tg mice. These results suggest that IGF-1 may enhance
the recovery from a demyelinating insult presumably by retaining the
mature oligodendrocyte population.
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MATERIALS AND METHODS |
Induction of demyelination. C57BL/6J wild-type mice
(Jackson Laboratory, Bar Harbor, ME) and IGF-1 tg mice were
maintained in our colony. The IGF-1 tg mice express IGF-1
under the mouse metallothionein-I promoter, and these mice were
backcrossed more than six generations onto the C57BL/6 background (Ye
et al., 1995). At 8 weeks of age, mice were fed a diet containing 0.2%
cuprizone (Sigma, St. Louis, MO) for 5 weeks to induce demyelination,
as described previously (Hiremath et al., 1998). Sham and
cuprizone-treated mice were killed weekly. The forebrains from the mice
were removed for morphological and biochemical analysis as described
previously (Coetzee et al., 1996; Ye et al., 1996; Mason et al., 2000).
Mice were maintained in sterile pathogen-free conditions under
Institutional Animal Care and Use Committee and University of North
Carolina Division of Laboratory Animal Medicine guidelines.
Immunohistochemistry. All comparative analyses were focused
in the corpus callosum on either side near midline. Frozen (10 µm) or
paraffin-embedded (5 µm) brain samples were cut in serial sections
between 220 and 260 in the mouse brain atlas (Sidman et al., 1971).
Frozen sections were stained either for IGF-1 using a rabbit anti-IGF-1
antibody (a gift from Dr. Underwood, Chapel Hill, NC) or for
oligodendrocyte progenitors using a rabbit anti-NG2 antibody (a gift
from Dr. Stallcup, San Diego, CA) as described previously (Mason et
al., 2000). No positive cell staining was observed in tissue sections
incubated with a control isotype-matched antibody (rabbit IgG; Vector
Laboratories, Burlingame, CA) in place of the primary antibody.
Paraffin-embedded sections were stained for the Pi isoform of
glutathione-S-transferase (GST-Pi; a mature oligodendrocyte marker), GST-Pi/apoptosis (apoptosis was detected using the Neurotacs assay kit from Trevigen), and Ricinus communis
agglutin-1 (RCA-1; a marker for
microglia/macrophages) as described previously (Hiremath et
al., 1998; Morell et al., 1998; Mason et al., 2000).
Cell number quantification.
RCA-1+,
GST-Pi+,
GST-Pi/apoptosis+, and
NG2+ cells from three to four mice were
quantified as described previously (Mason et al., 2000). Only
positive-stained cells containing a nucleus were quantified.
Electron microscopy. Glutaraldehyde-fixed brain samples
(three mice at each time point) were prepared as described previously (Coetzee et al., 1996). Coronal sections (1 µm) were stained with toluidine blue, and the medial region of the corpus callosum was identified by light microscopy. The tissue was then trimmed and reoriented for thin sectioning so that cross sections of the corpus callosum could be examined by electron microscopy. Thin sections were
cut, stained with uranyl acetate and lead citrate, and photographed, and then the electron micrographs were analyzed as described previously (Coetzee et al., 1996). Three hundred fibers (0.3 µm in diameter or
greater) from each mouse were examined.
Protein analysis. Total protein was extracted from the
forebrains of sham and treated mice as described previously (Ye et al.,
1996). Protein concentrations were determined using a protein assay kit
(Bio-Rad, Hercules, CA) with bovine serum albumin as the standard.
Quantification of IGF-1 protein was determined by radioimmunoassay as
described previously (Ye et al., 1996) using 20 µg of total protein.
Statistical analysis. Statistical comparisons were made
using a one-factor between-subjects ANOVA, followed by Tukey's test to
assess significance among groups.
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RESULTS |
Elevated expression of IGF-1 in transgenic mice
To determine IGF-1 expression in the corpus callosum of wild-type
mice, IGF-1 tg mice, and cuprizone-treated mice, IGF-1 RIA and immunostaining methods were used. IGF-1 protein levels were significantly (p < 0.01) greater in the
forebrains of untreated control IGF-1 tg mice (9.02 ± 1.40 ng/mg) compared with wild-type mice (3.83 ± 0.56 ng/mg).
This finding correlates with the presence of IGF-1 immunoreactivity
within the corpus callosum of IGF-1 tg mice compared with
the near absence of IGF-1+ cells in
wild-type mice (Figs.
1A,B).
At 3 weeks of cuprizone exposure, IGF-1 immunoreactivity appeared to
slightly increase relative to untreated controls in both the wild-type
and IGF-1 tg mice (Fig. 1C,D). By 5 weeks, intense IGF-1 immunoreactivity was elevated for the wild-type
mouse compared with untreated control (Fig. 1, compare A,
E). This cellular expression pattern is consistent with our
previous work demonstrating significant increase in IGF-1 protein by 4 and 5 weeks after the onset of mature oligodendrocyte apoptosis and
depletion (Mason et al., 2000). In contrast, the corpus callosum of
IGF-1 tg mice remained immunoreactive at 5 weeks but
appeared to display levels similar to that observed in untreated
IGF-1 tg mice (Fig. 1, compare B,
F). Nonetheless, IGF-1 persists in the forebrains of
IGF-1 tg mice throughout the 5 week cuprizone treatment
period.
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Figure 1.
Presence of IGF-1 within the corpus callosum of
wild-type and IGF-1 tg mice fed cuprizone. Frozen brain
sections from wild-type (A, C,
E) and IGF-1 tg (B,
D, F) mice were immunostained with
anti-IGF-1 (green). Although few
IGF-1+ cells were observed within the corpus
callosum of the untreated control wild-type mice
(A), a substantial number were observed in the
IGF-1 tg mice (B). At 3 weeks,
some IGF-1+ cells were present in wild-type mice
(C), whereas large numbers appeared in the
IGF-1 tg mice (D). At 5 weeks, a
large accumulation of IGF-1+ cells was observed in
the wild-type mice (E), whereas in IGF-1
tg mice the IGF-1+ cells appeared similar in
number to untreated control mice. Scale bar, 15 µm.
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Early recovery from acute demyelination in IGF-1
tg mice
Exposing adult mice to cuprizone results in demyelination and then
remyelination of the corpus callosum (Hiremath et al., 1998; Morell et
al., 1998). We examined whether the presence of IGF-1 during the first
5 weeks of cuprizone feeding could alter the demyelination process.
Morphometric analysis demonstrated that nearly all axons within the
corpus callosum were myelinated in both untreated control wild-type and
IGF-1 tg mice (Figs.
2A,B, 3). After 3 weeks of exposure to
cuprizone, the medial region of the corpus callosum was significantly
demyelinated in both the wild-type and IGF-1 tg mice (Figs.
2C,D, 3). In wild-type mice, this continued until
demyelination was nearly complete at week 5 (Figs.
2E, 3). In contrast, the medial region of the corpus callosum was substantially remyelinated in the IGF-1 tg mice
at 5 weeks (Figs. 2F, 3). These results suggest that
the demyelinating insult was not as extensive in the IGF-1
tg mice and that the recovery from the demyelinating insult
occurred earlier in these mice compared with wild-type mice.
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Figure 2.
Demyelination and remyelination in the corpus
callosum of IGF-1 tg and wild-type mice. Electron
micrographs show that nearly all axons within the corpus callosum are
myelinated in both the untreated wild-type (A)
and IGF-1 tg (B) mice. A large
number of axons are demyelinated in both the wild-type
(C) and IGF-1 tg
(D) mice exposed to cuprizone for 3 weeks. At 5 weeks, almost all of the axons are demyelinated in the wild-type mice
(E), whereas most of the axons are myelinated in
the IGF-1 tg mice (F). Scale bar,
1.2 µm.
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Figure 3.
Percentage of myelinated axons within the corpus
callosum of wild-type and IGF-1 tg mice. The percentage
of myelinated axons within the corpus callosum of mice was determined
by morphometric analysis of electron micrographs (300 axons per mouse
were examined). The mean and SEM bars are plotted for each time point
(n = 3) as examined in the wild-type (black
bars) and IGF-1 tg (white bars)
mice. (*p < 0.01; **p < 0.001 when comparing wild-type mice with IGF-1 tg mice.)
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Microglia/macrophage accumulation corresponds to demyelination
The accumulation of microglia/macrophages has been shown to be
associated with demyelinating lesions in the CNS of adult mice (Hiremath et al., 1998). Microglia/macrophages
(RCA-1+ cells) were very rare within the
corpus callosum of untreated wild-type and IGF-1 tg mice
(Figs.
4A,B,
5). By 3 weeks of cuprizone feeding,
microglia/macrophages began to accumulate in large numbers within the
corpus callosum of wild-type mice; however, even larger numbers
accumulated within the demyelinating lesion in the IGF-1 tg
mice (Figs. 4C,D, 5). By 5 weeks, very few
RCA-1-positive cells were observed within the remyelinating corpus
callosum of the IGF-1 tg mice, whereas a large number of
these cells remained in the demyelinated corpus callosum of the
wild-type mice at 5 weeks (Fig. 5). These results demonstrate that the
presence of microglia/macrophages correlates closely with the degree of
demyelination within the corpus callosum.
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Figure 4.
Microglia/macrophages associate with demyelination
within the corpus callosum of cuprizone-treated wild-type and
IGF-1 tg mice. Paraffin-embedded brain sections from
wild-type (A, C) and IGF-1
tg (B, D) mice were stained with
RCA-1. No RCA-1+ cells were observed in the
untreated control wild-type (A) and IGF-1
tg (B) mice. Large numbers of
RCA-1+ cells (brown stain) were
present in wild-type (C) and IGF-1 tg
(D) mice fed cuprizone for 3 weeks. Scale bar, 25 µm.
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Figure 5.
The accumulation of microglia/macrophages in the
corpus callosum of wild-type and IGF-1 tg mice during
cuprizone feeding. The number of RCA-1+ cells of
wild-type mice (black bars) and IGF-1 tg
mice (white bars) was quantitated in triplicate and
plotted as mean ± SEM (*p < 0.001 when
comparing wild-type mice and IGF-1 tg mice).
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Survival of mature oligodendrocytes during demyelination
The rapid recovery of the IGF-1 tg mice from
demyelination led us to postulate that the mature oligodendrocytes in
the IGF-1 tg mice may have survived the demyelinating
insult. Before treatment, wild-type and IGF-1 tg mice
appeared to have equal numbers of GST-Pi+
oligodendrocytes within the corpus callosum (Figs.
6A,B,
7A). After 3 weeks of exposure
to cuprizone, the number of GST-Pi+
oligodendrocytes was reduced by >50% in the wild-type mice (Fig. 6,
compare A with C and Fig. 7A), and by
week 5 they were severely depleted (Figs. 6E,
7A). In contrast, only a slight reduction in the number of
mature oligodendrocytes was observed in the IGF-1 tg mice
(Fig. 6, compare B with D and Fig.
7A). The presence of IGF-1 appeared to allow for the rapid
recovery of the mature oligodendrocyte population, because the number
of GST-Pi+ oligodendrocytes returned to
control levels by 4 and 5 weeks in the IGF-1 tg mice (Figs.
6F, 7A). These results suggest that mature
oligodendrocytes may be protected by the presence of IGF-1 before and
during acute demyelination within the brain.
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Figure 6.
Mature oligodendrocytes and apoptosis in the
corpus callosum of wild-type and IGF-1 tg mice.
Paraffin-embedded brain sections were immunostained with anti-GST-Pi
(green cells;
A-J), and some sections were also
examined for the presence of apoptotic cells (red
nuclei; G-J). Large
numbers of GST-Pi+ cells were observed in untreated
control wild-type (A) and IGF-1 tg
(B) mice. At 3 weeks of exposure to cuprizone,
there was a decrease in the number of GST-Pi+ cells
in wild-type mice (C), whereas only a slight
reduction was observed in the IGF-1 tg mice
(D). At 5 weeks, only a few
GST-Pi+ cells were observed in the wild-type mice
(E), whereas normal numbers of these cells were
observed in the IGF-1 tg mice (F).
No apoptotic cells were observed in the untreated control wild-type
(G) and IGF-1 tg
(H) mice. At 3 weeks, a large number of
apoptotic nuclei colocalized with GST-Pi+ cells
(arrow) in wild-type mice
(I), whereas no colocalization was
observed in the IGF-1 tg mice (J).
Scale bar, 25 µm.
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Figure 7.
Survival of mature oligodendrocytes in
IGF-1 tg mice. The number of GST-Pi+
mature oligodendrocytes (A) and the number of
apoptotic mature oligodendrocytes (B) were
quantitated for wild-type mice (black bars) and
IGF-1 tg mice (white bars) from
triplicate samples and plotted as mean ± SEM
(*p < 0.001 when comparing wild-type mice with
IGF-1 tg mice).
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We have shown previously that the depletion of the
GST-Pi+ population during
cuprizone-induced demyelination is likely attributable to the apoptotic
death of these cells (Mason et al., 2000). No apoptotic
GST-Pi+ oligodendrocytes were observed in
untreated control wild-type or IGF-1 tg mice (Figs.
6G,H, 7B). At 3 weeks of cuprizone
exposure, a large number of GST-Pi+
oligodendrocytes were undergoing apoptosis in the wild-type mice (Figs.
6I, 7B). This is consistent with previous
findings that most apoptotic mature oligodendrocytes were observed
between weeks 2 and 4 during exposure to cuprizone (Mason et al.,
2000). In contrast, very few apoptotic oligodendrocytes were observed
in the IGF-1 tg mice at week 3 (Figs. 6J,
7B). These results suggest that the presence of IGF-1 within
the CNS before acute demyelination appeared to keep mature
oligodendrocytes from undergoing apoptosis.
Absence of oligodendrocyte progenitors within the demyelinating
corpus callosum of IGF-1 tg mice
We have demonstrated previously that oligodendrocyte progenitors
accumulate and differentiate within lesions that were depleted of
preexisting mature oligodendrocytes, thereby leading to the repopulation of the mature oligodendrocytes (Mason et al., 2000). We
speculated that the survival of the mature oligodendrocytes within the
demyelinating lesion in the IGF-1 tg mice may inhibit the
ushering in of oligodendrocyte progenitors, although demyelination was
evident. Before cuprizone treatment, few oligodendrocyte progenitors were present within the corpus callosum of untreated control wild-type and IGF-1 tg mice (Figs.
8A,B,
9). However, a large number of oligodendrocyte progenitors began to accumulate within the
demyelinating corpus callosum in the wild-type mice at 3 weeks and
continued to increase during demyelination through week 5 (Figs.
8C, 9). In contrast, there was no accumulation of
oligodendrocyte progenitors within either the demyelinating corpus
callosum at week 3 or the remyelinating corpus callosum at weeks 4 and
5 in the IGF-1 tg mice (Figs. 8D, 9).
These results suggest that the activation and accumulation of the
oligodendrocyte progenitor population may be dependent on the absence
of the mature oligodendrocyte population and not demyelination. In
addition, these results also imply that the surviving mature
oligodendrocytes in the IGF-1 tg mice most likely permit the
early recovery from demyelination.
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Figure 8.
Accumulation of oligodendrocyte progenitors within
the corpus callosum of wild-type but not IGF-1 tg mice
during demyelination. Frozen brain sections from wild-type
(A, C) and IGF-1 tg
(B, D) mice were stained with the
anti-NG2 antibody (green). Few
NG2+ cells were observed in the untreated control
wild-type (A) and IGF-1 tg
(B) mice. Large numbers of
NG2+ cells were present in wild-type mice exposed to
cuprizone for 3 weeks (C). Few
NG2+ cells were observed in the IGF-1
tg mice fed cuprizone for 3 weeks (D).
Scale bar, 10 µm.
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Figure 9.
The accumulation of oligodendrocyte progenitors
within the corpus callosum of wild-type and IGF-1 tg
mice during cuprizone intoxication. The total number of
NG2+ cells was quantitated in the corpus callosum of
wild-type mice (white bars) and IGF-1 tg
mice (black bars) from triplicate samples and plotted as
mean ± SEM.
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DISCUSSION |
We have shown previously that mature oligodendrocytes are depleted
by apoptosis during cuprizone-induced demyelination (Mason et al.,
2000). In the present study, we have demonstrated several important
findings. (1) The presence of IGF-1 before acute demyelination in the
CNS appears to inhibit the apoptotic death and depletion of mature
oligodendrocytes; (2) significant primary demyelination can occur
despite survival of the mature oligodendrocyte population; (3) mature
oligodendrocytes surviving a demyelinating insult appear to retain the
ability to remyelinate; (4) the activation and accumulation of
oligodendrocyte progenitors appear to occur in response to the absence
of mature oligodendrocytes and not demyelination; and (5) the presence
of microglia/macrophages correlates with each of the demyelination
profiles for the wild-type and IGF-1 tg mice.
The present work showed that increased levels of IGF-1 did not inhibit
microglia/macrophage accumulation and acute demyelination within the
corpus callosum after exposure to cuprizone (Figs. 3, 5). In
fact, a greater number of microglia/macrophages and a slightly greater
degree of demyelination were observed in the corpus callosum of
IGF-1 tg mice at 3 weeks compared with the wild-type mice.
Our observations are contrary to findings using the EAE model of
demyelination (Liu et al., 1997). In EAE, the accumulation of
macrophages and the induction of demyelination were blocked in mice
given IGF-1 injections before a pathological insult. The authors
attributed this pathological inhibition to the ability of IGF-1 to
reduce the permeability of the blood-brain barrier (BBB) to immune
effector cells, particularly T-cells, during EAE (Liu et al., 1995).
This explanation may not be applicable because previous studies showed
that the BBB is not compromised during cuprizone feeding (Kondo et al.,
1987) and that T-cells play no significant role in cuprizone-induced
demyelination (M. M. Hiremath, K. Suzuki, J.P.-Y. Ting. G. K. Matsushima, unpublished observations). Thus, effects of IGF-1 on the
T-cell population and the BBB may not be relevant to cuprizone-induced demyelination.
The presence of IGF-1 early in the treatment period enhanced mature
oligodendrocyte survival. However IGF-1 did not prevent acute
demyelination. It is conceivable that the level of IGF-1 in the
IGF-1 tg mice adequately protects the cell body of mature oligodendrocytes from apoptosis; yet, if it is perturbed enough, this
may result in deterioration of the myelin sheath. Alternatively, during
exposure to cuprizone, apoptosis of mature oligodendrocytes may be
secondary to their lost contact with the axon, and IGF-1 may
temporarily substitute for the axonal survival signal. These findings
suggest that myelin pathology and mature oligodendrocyte death may be
independent processes. Nonetheless, increased levels of IGF-1 appear to
have a profound impact on the remyelination process. Demyelination
within wild-type mice progressed and then peaked at 5 weeks of
cuprizone feeding (Figs. 2C,E, 3), whereas remyelination was observed after 4 and 5 weeks in the IGF-1
tg mice (Figs. 2D,E, 3). These
results support a controversial issue that the surviving mature
oligodendrocytes are capable of remyelination. In addition, these
finding are consistent with previous observations in EAE in which
systemic injections of IGF-1, introduced after lesion formation,
resulted in reduced clinical deficits and lesion severity while also
upregulating the synthesis of myelin proteins (Yao et al., 1995, 1996).
This rapid recovery may have been caused by an increase in myelin
synthesis, the survival of the mature oligodendrocyte population, or a
combination of both.
Previous studies have recognized mature oligodendrocyte depletion as
the primary factor in the formation of chronic demyelinating lesions
(Johnson and Ludwin, 1981; for review see Raine, 1997; J. L. Mason, Hostettler JD, Morell P, Suzuki K, Matsushima GK unpublished observations). We have demonstrated that the depletion of
mature oligodendrocytes during cuprizone-induced demyelination is
attributable to the apoptotic death of these cells (Mason et al.,
2000). The present work, which demonstrates the ability of IGF-1 to
inhibit mature oligodendrocyte apoptosis in vivo (Fig. 7B), is consistent with previous in vitro studies
(Cho et al., 1997; Ye and D'Ercole, 1999). Although no or rare
apoptotic oligodendrocytes were observed, it is plausible that
apoptotic cells escaped our method of detection or sampling interval
that could have accounted for the slight reduction in the mature
oligodendrocyte population in the IGF-1 tg mice at 3 weeks.
Similarly, we cannot rule out the possibility that this reduction in
mature oligodendrocytes could be a consequence of necrosis and/or
dedifferentiation. However, our data suggest that inhibiting the death
of mature oligodendrocytes not only prevents their depletion, but it
may prevent the formation of chronic plaques in demyelinating diseases
such as multiple sclerosis.
IGF-1 tg mice when compared with wild-type mice displayed
dramatic differences in oligodendrocyte progenitor recruitment after demyelination. Wild-type mice showed an accumulation of oligodendrocyte progenitors within the demyelinating lesion (Fig. 8) consistent with
previous observations in the adult rodent CNS (Gensert and Goldman,
1997; Keirstead et al., 1998; Mason et al., 2000). In contrast,
there was no accumulation of oligodendrocyte progenitors within the
demyelinating lesion in the IGF-1 tg mice where mature oligodendrocytes remained present (Fig. 8). These results suggest that
the activation and/or accumulation of oligodendrocyte progenitors within a demyelinating lesion may be in response to the death or
absence of the mature oligodendrocyte population as observed in
wild-type mice and not caused by demyelination alone. Furthermore, the
surviving mature oligodendrocytes within the demyelinated lesion most
likely are responsible for the early remyelination observed in the
IGF-1 tg mice. These results imply that perturbed mature
oligodendrocytes regain their ability to myelinate when protected by
the presence of IGF-1. If IGF-1 is not present at sufficient levels, as
appears to be the case in wild-type mice, before treatment or during
the first 2 weeks of exposure to cuprizone, then mature
oligodendrocytes may become susceptible to an apoptotic death, which
eliminates their role in remyelination. In wild-type mice, exposure to
cuprizone results in oligodendrocyte death that progresses to their
near complete depletion from the corpus callosum, and remyelination is
primarily caused by the recruitment of oligodendrocyte progenitors that
eventually repopulate and differentiate within the lesions (Mason et
al., 2000). Our work here implies that mature oligodendrocytes are
capable of substantial remyelination of demyelinated axons. Combined
with previous in vitro (Cho et al., 1997; Ye and D'Ercole,
1999) and in vivo (Yao et al., 1996; Liu et al., 1997) studies, the present work strengthens the support for studying the
therapeutic merits of growth factors such as IGF-1 in demyelinating diseases.
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FOOTNOTES |
Received March 27, 2000; revised May 3, 2000; accepted May 3, 2000.
This work was supported in part by National Institute of Neurological
Disorders and Stroke Grants NS35372 (G.K.M.), NS24453 (K.S.), and
NS38891 (A.J.D.), and Grant RG2754A1 from the National Multiple
Sclerosis Society (G.K.M.), in the University of North Carolina
Neuroscience Center receiving core support from National Institute of
Child Health and Human Development Grant HD03110. We are
grateful to Dr. Robert Bagnell, Victoria Madden, and Clarita Langaman
for their assistance with the morphometric analysis.
Correspondence should be addressed to Dr. G. K. Matsushima,
University of North Carolina Neuroscience Center, CB# 7250, University of North Carolina, Chapel Hill, NC 27599. E-mail:
gkmats{at}med.unc.edu.
Dr. Mason's present address: Columbia University College of Physicians
and Surgeons, Department of Pathology, New York, NY 10032.
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ABSTRACT
INTRODUCTION
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