Research advancements of axonal remyelination in spinal cord injury

Journal o f Medical Colleges of P L A 2 0 0 7 ; 2 2 ( 4 )

250

Research advancements of axonal remyelination in spinal cord injury WU B o ( 8

@ I , REN Xian-jun" < { € % F )GUO , Shu-zhang(%@@)

Department o f Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China [Abstract]

Spinal cord injuries (SCI) usually result in impairment of axonal conduction and sensorimotor

function. There are no effective therapy to completely repair SCI. Axonal demyelination is very common as a pathologic change in SCI, and demyelination partly contributes to neural function impairment. So, it may be reasonable that remyelination of demyelinated axons become one of effective therapeutic targets for SCI treatment. Demyelination involves myelin breakdown and loss of myelin-forming cells (oligodendrocytes ). The death of oligodendrocytes plays a key role in axonal demyelination in SCI. Recently a number of studies demonstrate that cell replacements could facilitate axonal remyelination and restore axonal conductive function. Thus, it is expected that myelinogenetic cell transplantation (oligodendroglial lineage) will have good prospect as an effective therapy to improve axonal remyelination and restore neural function for SCI treatment in the near future.

[Key words]

spinal cord injury ; demyelination ; axonal remyelination

Spinal cord injury (SCI) has a high incidence

clinical setting, and the majority of SCI results

in central nervous system ( C N S ) , and usually re-

from avulsion or laceration. T h e lesion epicenter

sults in the impairment of axonal conduction and

predominantly locates in the gray matter, and then

sensorimotor function. U p to now, there is still no

lesion area gradually advances into white matter

effective therapy to repair SCI.

In the recent

region. Many researches have demonstrated that

years, basic researches focused on how to minimize

initial insult t o spinal cord usually causes damages

secondary injuries in SCI or t o spare more intact

to gray matter,

neural tissues, and how to promote neural regener-

progress into white matter. However, there are

ation or axonal regrowth"'.

Myelin is an essential

more or less some intact tissues left even at the

and then secondary injuries

component which wraps intact axons and conducts

level of the epicenter. Some white matter tissues

neural impulse on axon. Demyelination is recog-

underneath spinal pia mater usually surviveC51.

nized as universal pathologic alteration in SCI,

Nevertheless, the survived neural fibers subse-

which involves myelin breakdown and loss of

quently suffer from local inflammation and de-

myelin-forming cells. It has been proved that ax-

myelination because of oligodendrocyte deathC6].A

onal demyelination partly contributes to the func-

recent study on the pathologic changes following

tional impairment of CNSC1]. Remyelination of de-

dog' s SCI demonstrated that SCI mainly resulted

myelinated axons may be reasonably supposed as

from contusion and compression, which directly

one of therapeutic targets for neural functional re-

caused infarction and haemorrhage in gray matter.

covery of SCI.

The lesion then developed from gray matter to

Axonal demyelination in SCI

Axonal de-

myelination is commonly observed as a pathologic change in a number of CNS diseases, including brain trauma, multiple sclerosis, schizophrenia, normal aging, and SCI as

In fact, com-

plete transection of dorsal column rarely occurs in

white matter, and gave rise to swelling of neural axons and axonal degeneration. However, some white matter beneath the surface of spinal pia mater was spared intact. While axonal demyelination was detected within first 2 weeks after injury, schwann cells and oligodendroglial cells began to remyelinatec71.

*

:Corresponding author. Tel: 86-23-68774081

Another research observed the processes of

Journal of Medical Colleges o f PLA 2007;22(4)

251

axonal demyelination and remyelination in a rat

epicenter, and within nearby white matter. Fur-

SCI model for 450 d. These findings revealed that

ther study about origin of apoptotic cells demon-

there were large loss of neural tissue and extensive

strated the coexistence of oligodendrocyte-specific

axonal demyelination a t lesion site 1 week after

immunoractivity and apoptotic nuclear

SCI. Small amount of gray matter surrounded by

The

above-mentioned

findings

collectively

inflammatory cells, cavities a s well a s extracellular

suggest that axonal demyelination is a n important

matrix at the epicenter was left. A rim of white

pathological change in S C I , and death of oligoden-

matter tissue retained in the subpial region while

drocyte plays a role in axonal demyelination. De-

lymphocytes and macrophages dispersed along de-

myelination impairs saltatory conduction on axon.

generative axons. T h e composition a t lesion site

Hence, promoting axonal remyelination is of sig-

transformed to proliferative glia and extracellular

nificance to restore neural function in SCI.

fibers 70 d later. Quantitative analysis showed

Significance of axonal remyelination in SCI

that the total number of demyelinated axons grad-

Chronic demyelination in SCI is characterized with

ually increased with time. It was also founded that

loss of oligodendrocytes. Since demyelination and

oligodendrocytes and schwann cells remyelinated

other pathologic changes simultaneously occur in

axons in the same study. However, such remyeli-

injured spinal cord, it is impossible t o accurately e-

nation was not sufficient for functional recovery.

valuate whether axonal demyelination mainly con-

Meanwhile, demyelinated axons were present a t

tributes t o impairment of neural functions in SCI.

any time point. From above findings, it may ap-

However, axonal remyelination could be an impor-

propriately conclude that axonal demyelination in

tant therapeutic strategy for repairing SCI. In a

SCI is a chronic and progressive pathologic pro-

myelin-deficient rat SCI model, glial transplanta-

cessE8j.

tion into neonatal rats enhanced myelin formation,

T h e consequences of SCI are loss of neurons,

and conduction velocity of lesioned axons increased

death of myelin-producing oligodendrocytes as well

by 3 folds. Impulse passed through the transplan-

as subsequent axonal demyelination.

tation s i t e , and the response of neural fibers t o

Previous

studies documented that spinal cord injury resulted

stimuli became betterC133.Moreover, several ani-

in white matter degeneration and death of intrafas-

mal or clinical experiments also demonstrate that

cicular oligodendrocytes in a rat modelCg1. In an-

complete loss of sensorimotor function occurs occa-

other rat SCI experiment, it also found that initial

sionally, and some neural axons are left intact in

insult to dorsal column directly caused loss of tis-

lesion area. With regard t o complete S C I , the dor-

sue and apoptosis of neural cells, and in this ex-

sal column of patient is not transected anatomical-

periment apoptotic cells were found present in the

ly. In fact, demyelination of spared axons may af-

lesion areas, especially in white matter. In a mon-

fect conductive function of spinal cord t o some de-

key SCI model experiment, cellular apoptosis was

greeC14'. MRI and anatomical investigation also in-

also observed in the distant degenerative neural

dicated about 6 5 % of patients with complete SCI

fasciculi"''.

Furthermore, apoptosis of oligoden-

drocyte temporally related with secondary injuries in SCI.

retained some normal axons in the lesion areasC5*

153.

In a study of cat SCI model, weight drop in-

Some reported that oligodendroglial apoptosis

jury t o mid-thoracic segments induced hindlimb

could be detected within 24 h postinjury, and such

paralysis. Some intact axons ( 4 0 000-110 0 0 0 )

phenomenon further lasted for a t least 3 weeksc"j.

with normal myelin could be histologically ob-

Another clinical experiment analyzed the spinal

served present in the lesion a r e a , and the majority

cord tissues from the subjects who died within 3 h

distributed in the subpial region. Some animals

t o 8 weeks after initial injury. It revealed that the

with 5%-10% neural fibers left a t epicenter, and

apoptotic cells were found on the border of lesion

correspondingly displayed some functional recov-

Journal o f Medical Colleges o f P L A 2007;22(4)

252 ery. This study suggests that some intact tissue

ment into rat lesioned corticospinal tract, and the

spared in SCI is necessary for later functional re-

transplanted cells could encouraged axonal regen-

In other words, paraplegic patients

eration. The newly-formed myelin wrapped regen-

may benefit from the preserved neural fibers,

erative axons, and accompanied them growing into

which act as anatomical base for further functional

distal white matter across lesion site"g1.

coveryr6'15'.

improvement. In a study of guinea pig SCI, it was

Bone marrow stem cells (MSCs) have been

( potassium

widely studied as these cells can differentiate into

channel blocker 1 intervention could play a partial

several types of mature cell under certain condi-

role in recovering neural conduction after SCI"63.

tion,

investigated

that

4-aminopyridine

including neural cell lineage.

Some re-

Collectively, these findings indicate that pro-

searchers reported MSCs from adult rat femoral

moting axonal remyelination and recovery of con-

bone were intravenously infused to treat demeyli-

ductive function may be an effective strategy for

nated lesion of spinal cord. Ultrastructure analysis

SCI treatment. Experimental studies of axonal remyelination after SCI Recent studies indicate that cell re-

indicated that new myelin was produced in the demyelinated areas, and the newly-formed myelin

placement is able to facilitate axonal remyelination

cells and oligodendrocytes. Meanwhile, axonal re-

and restore axonal conductive function. Cell trans-

myelination also improved the conduction velocity

plantation therapy also improves axonal regenera-

of dorsal columnCzo1.

had the constructional features of both schwann

tion and neural function. Cells for transplantation

Stem cell is well known with pluripotential of

include schwann cells, olfactory ensheathing cells,

differentiation and capacity of unlimited prolifera-

oligodendrocyte precursors and embryonic or neu-

tion. An in vitro study displayed that mouse em-

ral stem cells.

bryonic stem cells (ESCs >-derived oligodendroglial

Some studies examined human sural nerve-de-

cells could remyelinate neural axons after trans-

rived schwann cell transplantation to treat X-ray

plantation. These cells were transplanted into de-

radiation SCI in Wister rat model. In 3-5 weeks af-

myelinated regions 3 days after rat SCI, The im-

ter implantation,

and

planted cells survived at the lesion site, and fur-

myelin widespreadly formed in lesion areas. An in

ther differentiated into mature oligodendrocytes

vitro study further revealed partial conductive

with newly-formed myelin ensheathing denuded

function recovered. The dorsal column displayed

axons. In addition, these cells were further trans-

improved conduction velocity and frequency-re-

planted into myelin-deficient shiverer mice (shi/

sponse properties. These data support that trans-

shi) , and evident survival of implanted cells was

schwann cells survived

plantation of schwann cells can enhance functional remyelination after

scP7].

also detected. These transplanted cells migrated within spinal cord and myelinated host axonsC211.

Olfactory ensheathing cells (OECs

are spe-

Furthermore, human embryo-derived or adult

cialized glial cells with myelin-forming capacity.

oligodendrocyte progenitor cells (OPCs ) were re-

They normally myelinate axons of olfactory nerve,

cently studied about their potential as transplant in

and assist olfactary nerve to grow into CNS. In an

the myelin-deficient model of shiverer mice. After

adult rat SCI model, the transplanted adult human

embryonic OPCs transplanted into newborn mice

OECs were able to cause extensive new mylin for-

forebrains, the transplanted cells could survive

mation. In situ hybridization with human DNA

well and disperse in the white matter, and then

probe ( COT-1 ) revealed COT-1 positive OECs

matured

survived in the transplantation site. The ultra-

Twelve weeks after transplantation, extensive ax-

structure of newly-formed myelin resembled the

onal remyelination was apparent in the host

myelin OECs"''.

features

of

both

schwann

cells

and

An early study analyzed OECs engraft-

brains.

into

oligodendrocytes

or

astrocytes.

Adult OPCs also formed new myelin in

shiverer mice brain post-implantation

,

and inter-

Journal o f Medical Colleges of PLA 2007 ;22(4)

253

estingly the remyelination process was sooner than

tion in transplantation s i t e , and no evidence of

that of embryonic OPCs. Myelin basic protein was

neurophysiologic deterioratation or occurrence of

4

posttrans-

neuropathic pain. T h e functional recovery via cel-

plantationCz2'. Some studies further demonstrated

lular transplantation will be finally concluded by

that myelin-forming cells also worked in primate

t h e end of whole 3-year trial. These preliminary

SCI model, which provided valuable evidence for

results indicate that autologous OECs transplanta-

future clinical application of cell transplantation.

tion for clinical SCI treatment is safe and feasi-

This experiment used porcine OECs to treat de-

bleCZ6'.

extensively

expressed

weeks

myelination in African green monkey. Four weeks

Taken together, axonal demyelination in SCI

after transplantation, 62. 5 % subjects demonstrat-

is a chronic and progressive pathologic process. T o

ed prominent axonal regeneration in the implanta-

facilitate axonal remyelination after SCI and re-

tion site, whereas the control groups did not show

store neural conduction is considered a s potentially

definite myelin formationCz3'.

attractive therapeutic intervention for SCI treat-

These findings together demonstrate that pro-

ment. Myelinogenetic cell transplantation may be-

moting axonal remyelination can partially restore

come an alternative of treatment strategies for the

neural functions in SCI. Some researches reported

functional recovery of SCI in the future.

that myelinogenetic cell transplantation treated myelin-deficient lesion of rat spinal cord, and new-

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