Neuroscience Research 126 (2018) 39–43

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Neuroscience Research
journal homepage: www.elsevier.com/locate/neures

Review article

Astrocyte reactivity and astrogliosis after spinal cord injury

Seiji Okada a,b,∗ , Masamitsu Hara a,b , Kazu Kobayakawa b , Yoshihiro Matsumoto b ,
Yasuharu Nakashima b
a
Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
b
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

a r t i c l e i n f o a b s t r a c t

Article history: After traumatic injuries of the central nervous system (CNS), including spinal cord injury (SCI), astrocytes
Received 25 August 2017 surrounding the lesion become reactive and typically undergo hypertrophy and process extension. These
Received in revised form 9 September 2017 reactive astrocytes migrate centripetally to the lesion epicenter and aid in the tissue repair process,
Accepted 9 September 2017
however, they eventually become scar-forming astrocytes and form a glial scar which produces axonal
Available online 17 October 2017
growth inhibitors and prevents axonal regeneration. This sequential phenotypic change has long been
considered to be unidirectional and irreversible; thus glial scarring is one of the main causes of the limited
Keywords:
regenerative capability of the CNS. We recently demonstrated that the process of glial scar formation is
Spinal cord injury
Astrocytes
regulated by environmental cues, such as fibrotic extracellular matrix material. In this review, we discuss
Glial scar the role and mechanism underlying glial scar formation after SCI as well as plasticity of astrogliosis, which
Axonal regeneration helps to foster axonal regeneration and functional recovery after CNS injury.
Laser microdissection © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Contents

1. Spinal cord injury and glial scar formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

2. The beneficial role of reactive astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3. The plasticity of astrocytic changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4. Preventing glial scar formation through environmental regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
5. Cell transplantation therapy and glial scar for SCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

in the USA; approximately 100,000 people in Japan and 1.2 million

1. Spinal cord injury and glial scar formation people in the USA are paralyzed due to SCI, mainly because of motor
vehicle, sports, and work accidents (Lee-Liu et al., 2013; Ide-Okochi
There are approximately 5000 new cases of traumatic spinal et al., 2013). The incidence of fall-related injuries in the elderly pop-
cord injury (SCI) recorded each year in Japan, and 17,000 new cases ulation has significantly increased with the aging of the population
(Okada et al., 2009). Traumatic SCI often causes irreversible motor
and sensory dysfunction as well as the loss of bladder, bowel and
sexual function, resulting in a significant reduction in the quality
Abbreviations: CNS, central nervous system; SCI, spinal cord injury; USA, United
States of America; GFAP, glial fibrillary acidic protein; STAT, signal transducer
of life (Adams and Hicks, 2005). Since there are no approved ther-
and activator of transcription; SOCS, Suppressor of cytokine signaling; LMD, laser apies to restore the spinal cord function, a better understanding of
microdissection; GFP, green fluorescent protein; FACS, fluorescence activated cell the mechanism for compromising functional recovery after SCI is
sorting; Col I, the type 1 collagen; NAs, naïve astrocytes; RAs, reactive astrocytes; significantly important.
SAs, scar-forming astrocytes.
∗ Corresponding author at: Department of Orthopaedic Surgery, Graduate School
Glial scarring, which impedes axonal regeneration and func-
of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-
tional recovery has been considered to be the main cause of the
8582, Japan. limited regenerative capability in the mammalian CNS (Silver and
E-mail address: seokada@ortho.med.kyushu-u.ac.jp (S. Okada). Miller, 2004). The impeded axonal regeneration and functional

https://doi.org/10.1016/j.neures.2017.10.004
0168-0102/© 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
40 S. Okada et al. / Neuroscience Research 126 (2018) 39–43
Fig. 1. The changes of astrocytes after CNS injury. Naïve astrocytes are activated by
several types of injury (i.e., inflammation, infection, ischemia, and traumatic injury)
and they exhibit sequential phenotypic changes, including cellular hypertrophy and
process extension; these are referred to as reactive astrocytes. Around the area of
the lesion, reactive astrocytes express cell adhesion molecules, such as N-cadherin,
and transform into scar-forming astrocytes. Scar-forming astrocytes adhere to each
other and form the glial scar.
recovery have been shown to be irreversible and to permanently
inhibit axonal regrowth in both rodents and humans with SCI (Lee-
Liu et al., 2013). In fact, in some non-mammalian vertebrate animals
(i.e., urodele amphibians and lampreys) in which little glial scar
formation is detected, the spinal cord has been shown to regener-
ate, substantially restoring the motor function (Lee-Liu et al., 2013;
Diaz Quiroz and Echeverri, 2013). Chondroitin and keratin sulphate
proteoglycans are among the main inhibitory extracellular matrix
molecules to be produced by reactive astrocytes in glial scars, and
they play a crucial part in regeneration failure (Silver, 2016). Due
to the presence of these inhibitory molecules, severed axons can-
not regenerate past the lesion. In fact, after SCI, treatment with
chondroitinase results in the degradation of chondroitin sulphate
proteoglycans at the lesion site and allows axonal regeneration and
functional recovery (Bradbury et al., 2002).
Glial scar formation after CNS insult is regulated by complex and
combinatorial inter- and intracellular signal mechanisms. Under
normal conditions, astrocytes are the predominant subtype of glial
cells in the CNS; they maintain neurons as well as the blood-brain-
barrier. They are activated in response to various types of injury,
including inflammation, infection, ischemia, and traumatic injury,
and play a crucial role in the pathophysiology of each through
a phenotypic change known as reactive astrogliosis. After SCI,
naïve astrocytes sequentially exhibit contrasting phenotypes, first
as reactive astrocytes and then as scar-forming astrocytes (Fig. 1).
Although the mechanism underlying reactive response of naïve
astrocytes has not been fully elucidated, Shinozaki et al., recently
have demonstrated that microglia transformed astrocytes pheno-
type via downregulation of the P2Y1 purinergic receptor (Shinozaki
et al., 2017). Reactive astrocytes are necessary in the acute wound
healing and tissue remodeling processes; however, they eventu-
ally become scar-forming astrocytes and form a dense glial scar.
Although these different astrocytic functions are multifaceted and
phase-dependent, the term of astrogliosis has only been roughly
defined, which makes the role of astrocytes unclear in the patho-
physiology of SCI.
2. The beneficial role of reactive astrocytes
Although limited functional recovery occurs during the chronic
phase of SCI, temporary functional recovery is often observed soon
after incomplete SCI (Kobayakawa et al., 2014). The mechanism
underlying this phenomenon has been unclear. We previously
demonstrated that the astrocytic responses are crucial to tissue
repair and functional recovery after SCI (Okada et al., 2006). We
first created a contusive SCI (70 Kdyn) on the mouse 9th tho-
racic spinal cord using a commercially available SCI device (Infinite
Horizons Impactor, Precision Systems Instrumentation, Lexington,
KY), performed an immunohistological analysis, and evaluated the
functional recovery. In this model of incomplete SCI, there was a
substantial recovery in lower extremity movement until 2–3 weeks
after injury. During this functional recovery phase, we found that
reactive astrocytes emerged and eventually migrated centripetally
to the area of the lesion and compacted the infiltrating inflamma-
tory cells, resulting in the compaction of the area of the lesion.
After the migration of reactive astrocytes and the completion of
glial scar formation, the functional improvement also reached a
plateau. Although reactive astrocytes were considered to be harm-
ful for the pathophysiology of SCI due to their contribution to glial
scar formation, this phenomenon indicates that the emergence
and migration of reactive astrocytes had a prominent role in the
repair of injured tissue and the restoration of the motor function
before the completion of glial scar formation (Okada et al., 2006). In
fact, selective ablation of dividing astrocytes using ganciclovir after
SCI in the GFAP-TK transgenic mice resulted in severe leukocyte
infiltration, tissue disruption, demyelination and neuronal death
(Faulkner et al., 2004), which also suggested the beneficial role
of reactive astrocytes after SCI. Since we found that phosphory-
lation and nuclear translocation of signal transducer and activator
of transcription-3 (STAT3) were mainly observed in reactive astro-
cytes, we examined the role of STAT3 in reactive astrocytes in the
mouse model of SCI (Okada et al., 2006). In the genetically modified
mice in which STAT3 was selectively depleted in reactive astro-
cytes under the control of Nestin gene promoter/enhancer, reactive
astrocytes showed limited migration to the lesion epicenter, which
resulted in a wide area of injury, impaired contraction of infiltrating
inflammatory cells, and limited functional recovery (Fig. 2). Sim-
ilar results were observed after SCI in the STAT3-depleted mice
in GFAP-expressing astrocytes, indicating that STAT3 is a critical
regulator of astrogliosis (Herrmann et al., 2008). In contrast, in
the genetically modified mice in which the protein suppressor of
cytokine signaling-3 (SOCS3, negative feedback molecule of STAT3)
was selectively depleted in reactive astrocytes, the rapid migration
of reactive astrocytes to secluded inflammatory cells, enhanced
contraction of the area of the lesion, and a dramatic improve-
ment in functional recovery were observed after SCI. Similarly, in
transgenic mice that showed the expression of astrocyte-targeted
interleukin-6 (IL-6, one of the upstream effectors of STAT3 path-
way) the prompt migration of reactive astrocytes and compaction
of infiltrating inflammatory cells were observed after CNS injury
(Penkowa et al., 2003). These result suggest that STAT3 signaling,
which is associated with the migration of reactive astrocytes, is a
key regulator in the healing process after SCI. In contrast, in the
chronic phase of injury, reactive astrocytes form glial scars, which
function as a physical and chemical barrier, impairing axonal regen-
eration.
3. The plasticity of astrocytic changes
Although astrocytic scars have been studied for more than half
a century, the cellular and molecular mechanisms of this pro-
cess remain unclear. One factor that limits basic research is the
absence of specific markers of differentiation and reactivity. For
example, the characterization of astrocytes is usually performed
using intermediate filament GFAP; however, all phenotypes of
astrocytes including reactive astrocytes and scar-forming astro-
cytes are strongly expressed with GFAP, even though these cell
types show distinct morphological characteristics. These cells are
conventionally distinguished from each other based on a histo-
logical analysis. Reactive astrocytes are characterized by cellular
hypertrophy, process extension, and the increased expression of
intermediate filaments such as GFAP and Nestin (Frisén et al.,
1995). However, this immunohistological discrimination is neither
objective nor quantitative. To investigate the regulatory mecha-
nism underlying astrogliosis, clear definitions for naïve, reactive,
and scar-forming astrocytes are necessary; we therefore developed
 S. Okada et al. / Neuroscience Research 126 (2018) 39–43
Fig. 2. The beneficial role of reactive astrocytes in SCI. The migration of reactive astrocytes is important for tissue repair and functional recovery. The impaired migration of
reactive astrocytes results in a wide lesion and poor functional recovery.
a method for distinguishing these cells based on the expression
of marker genes by selectively isolating these cells with laser
microdissection (LMD) (Hara et al., 2017). Naïve astrocytes were
isolated from the intact spinal cord, while reactive astrocytes from
the spinal cord of B6 mice in the subacute phase of injury (7 days
after a contusive injury [70 Kdyn]), and scar-forming astrocytes
were isolated from the chronic phase of injury (14 days after the
same SCI). This method revealed that in reactive astrocytes, Nes,
Ctnnb1, Axin2, Plaur, Mmp2, Mmp13 were selectively upregulated
in comparison to naïve and scar-forming astrocytes. These genes
were therefore defined as the marker genes of reactive astrocytes.
Similarly, Cdh2, Sox9, Xylt1, Chst11, Csgalnact1, Acan, Pcan, Slit2 were
defined as the marker genes of scar-forming astrocytes. The com-
bination of the expression profile of these marker genes and the
morphological definitions is useful for identifying the phenotype
of astrocytes. Using these markers, we examined whether glial scar
formation represented a cell-autonomous phenotypic change or a
non-cell-autonomous change (Hara et al., 2017).
First, we harvested the green fluorescent protein (GFP)-labeled
naïve astrocytes from primary astrocyte cultures of the green
mice where GFP is ubiquitously expressed and then transplanted
them into the spinal cords of either naïve mice or mice with
SCI, immediately after spinal contusion. At 7 and 14 days after
transplantation, we examined the morphological and immuno-
histochemical characteristics of grafted cells as well as the gene
expression by cell-selective isolation with LMD. The morphological
and gene expression characteristics of the grafted cells were both
unchanged when they were grafted into the naïve spinal cord. In
contrast, the grafted cells transformed along with host astrocytes
during various processes, such as process extension and cellular
hypertrophy, and the reactive astrocyte marker genes were sig-
nificantly upregulated in the injured spinal cord at 7 days after
transplantation; they gradually overlapped and were integrated
into astrocytic scars and scar-forming astrocyte marker genes were
significantly upregulated at 14 days after transplantation. These
findings suggest that astrocytes change their phenotype in an
environment-dependent manner. Next, we examined the plastic-
ity of the sequential astrocytic changes and whether the reactive
astrocytes could revert back to naïve astrocytes after transplan-
tation into the naive spinal cord. We selectively isolated reactive
astrocytes that were genetically-labeled with GFP under the Nes
41
promotor using FACS from 7 days after spinal cord injury, and
confirmed that the reactive astrocyte marker genes were upreg-
ulated in these isolated cells. We then grafted these GFP-positive
reactive astrocytes into a new cohort of mice in which the spinal
cord was either intact or injured. Notably, the engrafted reac-
tive astrocytes formed astrocytic scars when transplanted into the
injured spinal cord, whereas they reverted (morphologically) back
to naïve astrocytes when transplanted into the naïve spinal cord
(Fig. 3). Consistent with the morphological conversion, a selective
gene expression analysis of the engrafted cells using LMD demon-
strated that scar-forming astrocyte marker genes were significantly
upregulated at 7 days after transplantation when the cells were
transplanted into the injured spinal cord. In contrast, the original
expression patterns of reactive astrocyte marker genes were sig-
nificantly suppressed when they were transplanted into the naïve
spinal cord. In addition, a whole-transcriptome analysis of isolated
reactive astrocytes, reactive astrocytes transplanted into the naïve
spinal cord (at 7 days after transplantation), and host astrocytes
in the naïve spinal cord, revealed that the global gene expression
profiles of transplanted and host astrocytes were comparable; how-
ever, they were markedly different from the global gene expression
profiles of isolated reactive astrocytes. These results clearly indi-
cated that the process of reactive astrogliosis is reversible under
certain conditions (Hara et al., 2017).
4. Preventing glial scar formation through environmental
regulation
As described above, reactive astrocytes have beneficial func-
tions, while scar-forming astrocytes are harmful to the repair
process after SCI (Okada et al., 2006). Thus, preventing the transfor-
mation of reactive astrocytes into scar-forming astrocytes through
environmental modification may be a new therapeutic strategy for
SCI. To detect the environmental cues associated with the trans-
formation of reactive astrocytes into scar-forming astrocytes, we
performed time-course genome-wide expression analyses in naïve
and injured spinal cord models. These analyses revealed that in
comparison to the naïve spinal cord, the type 1 collagen (Col I)
genes were the more highly expressed in the injured spinal cord
during the scar forming phase (Hara et al., 2017). We performed an
immunohistochemical analysis to investigate the influence of Col
42 S. Okada et al. / Neuroscience Research 126 (2018) 39–43

Fig. 3. The plasticity of astrocytic change. The engrafted reactive astrocytes formed astrocytic scars when transplanted into the injured spinal cord, whereas they reverted
to naïve astrocytes when transplanted into the naïve spinal cord, indicating that the process of reactive astrogliosis occurs in an environment-dependent manner and has
plasticity.

Fig. 4. Preventing glial scar formation through environmental regulation. The administration of anti-␤1 Ab during the scarring phase inhibited the interaction between Col
I and RAs as well as the transformation of RAs to SAs, which resulted in loosened scar formation. Axonal regeneration at the glial scar was impeded in the control group
whereas axonal regeneration into and beyond the epicenter of the lesion was observed in the treatment group.

I on the fate of reactive astrocytes in vitro; the analysis revealed
that astrocytic scars were formed by scar-forming astrocytes colo-
calised with the expression of Col I, while the reactive astrocytes
retained their phenotypes in the Col I-absent area. Reactive astro-
cytes showed process retraction and the decreased expression of
GFAP when cultured in control dishes. In contrast, they adhered
closely to adjacent cells and showed the increased expression of
GFAP and N-cadherin (characteristic of scar-forming astrocytes),
when cultured on Col I-coated dishes. Interfering in the interaction
between reactive astrocytes and Col I using antibodies to collagen-
binding integrin (anti-␤1 Ab) as well as N-cadherin-neutralizing
antibodies, inhibited the transformation of reactive astrocytes into
scar-forming astrocytes, even when they were cultured on Col I-
coated dishes. This suggests that Col I induces the transformation
of reactive astrocytes into scar-forming astrocytes via the integrin-
N-cadherin pathway. Similarly, the administration of anti-␤1 Ab
during the scarring phase after SCI loosened the scar formation and
allowed for significant axonal regeneration into and beyond the
epicenter of the lesion, which resulted in better functional recovery
in comparison to the control SCI mice (Fig. 4). These results indicate
that environmental modification in the injured spinal cord pre-
vents astrocytic scar formation and promotes axonal regeneration
and functional recovery after SCI, providing a potential therapeutic
target for CNS injury (Hara et al., 2017).
5. Cell transplantation therapy and glial scar for SCI
In recent years, cell transplantation has emerged as a potential
therapeutic strategy for SCI and several early-phase clinical trials
have been completed. Their results showed that cell transplan-
tation is generally feasible; however, the efficacy and long-term
safety remain unproven (Assinck et al., 2017). Notably, most
preclinical and experimental transplantation studies have been
performed in the acute or subacute phase of SCI; few studies
have investigated the initiation of treatment in the chronic phase.
In addition, transplantation was reported to be effective in the
acute or subacute phase of SCI in experimental models. Moreover,
few studies have shown its efficacy in chronic SCI—even in ani-
mal experimental models. In fact, Fehlings’ group reported that
the transplantation of neural precursor cells improved the func-
tional recovery in the subacute phase of SCI, but not in the chronic
phase (Karimi-Abdolrezaee et al., 2006). We also have reported that
chronic transplantation of neural precursor cells failed to improve
functional recovery although their engraftment, neuronal differen-
 S. Okada et al. / Neuroscience Research 126 (2018) 39–43
tiation potential, trophic factor secretion were comparable to those
of the acute transplantation (Kumamaru et al., 2013). Considering
that the engrafted neural precursor cells promote functional recov-
ery through synapse reorganization with spared host neurons after
SCI (Yokota et al., 2015), the failure of the chronic transplantation
can likely be ascribed to the glial scar, which strictly segregates the
lesion and the spared area after SCI. Since the demand for therapies
that are effective for chronic SCI is much greater than that for acute
SCI, a combined approach of cell transplantation therapy with the
attenuation of glial scarring is needed.
6. Concluding remarks
In this review, we concisely summarized the pathophysiology as
well as the reversibility of astrogliosis after SCI with an emphasis on
the selective analysis of each astrocyte phenotype. The regulation of
astrogliosis and the transition of naïve, reactive, and scar-forming
astrocytes could be a feasible and novel therapeutic strategy for SCI.
However, a therapeutic approach for chronic SCI, that either atten-
uates or eliminates a glial scar after it has already formed is most
needed. In addition, the precise mechanism of functional recovery
by promoting the migration of reactive astrocytes and attenuat-
ing glial scar formation remains elusive, since the reorganization
of interactions between descending inputs from the brain to the
spinal cord neurons controlling paroxysmal muscles is required.
Further elucidation of the astrocytic response during neuronal cir-
cuit restoration will provide a better understanding of the glial
biology and a novel therapeutic strategy for CNS injury.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgments
This study was supported in part by a Grants-in-Aid for Scien-
tific Research (16H05450) and Challenging Exploratory Research
(16K15668) from the Ministry of Education, Science, Sports and
Culture of Japan.
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