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Star-cross’d neurons: astroglial effects on neural repair
in the adult mammalian CNS
Jason G. Emsley*, Paola Arlotta* and Jeffrey D. Macklis
MGH-HMS Center for Nervous System Repair, Departments of Neurosurgery and Neurology, and Program in Neuroscience,
Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA
Astroglia have long been thought to play merely a supporting role in the life of the neuron. However, these
star-shaped cells have recently been the focus of
intense study that has begun to emphasize remarkable
and novel roles for these amazing cells. While astroglia
play positive roles in the life of the neuron, they can
simultaneously exert negative influences. Kinouchi et al.
convincingly demonstrate and characterize an inhibitory role played by astroglia after neuronal transplantation. These findings remind us that astroglia exert
positive and negative influences on neuronal survival,
migration, neurite outgrowth and functional integration. Here, we review the complementary and
often contradictory roles of astroglia during neuronal
integration.
Long considered mere passive or supportive cells, capable
of providing only growth factors or trophic factors to
neighbouring neurons, glia have recently been the object of
intense study that has begun to emphasize remarkable
and novel roles for these amazing cells in the brain. Among
the most notable and provocative studies are those proposing that ‘astroglia-like’ cells [i.e. cells showing phenotypic and/or antigenic features of astrocytes, including
cytoplasmic glycogen inclusions and expression of the
intermediate-filament protein glial-fibrillary acidic protein (GFAP)] from neurogenic regions such as the adult
subventricular zone or dentate gyrus might be neural
precursors or ‘stem cells’, capable of giving rise to neurons
[1 – 4]. Other studies have shown that the star-shaped
astroglia might also play crucial roles in defining a
molecular niche supportive for neurogenesis in vivo [5].
* These authors contributed equally to the article.
Corresponding author: Jeffrey D. Macklis ([email protected]).
www.sciencedirect.com
Thus, astroglia might nurture, or a subset of related cells
might even produce, neurons, which were long thought to
be the lords to supportive astroglial serfs.
However, just as astroglia play positive roles in the life
of the neuron, they can simultaneously exert negative
influences. Indeed, the inhibitory roles of astroglia upon
nerve regeneration are now well documented; glial scars
that typically form after injury by reactive astrocytes
constitute both a mechanical and a chemical barrier that
blocks nerve regeneration and axonal growth. Now,
Kinouchi and colleagues [6] provide further compelling
evidence for the central role of astroglia in neuronal
differentiation and integration in the adult CNS.
Robust neuronal integration in a modified astroglial
environment
In this elegant study, the authors used the adult mammalian retina, which contains both astroglia and Müller
glia, as a model in which to characterize and assess how
astroglia can influence neuronal integration. Kinouchi
et al. provide crucial insight into the molecules that control
this phenomenon. Specifically, and most interestingly,
they show that two classically astroglial filament proteins,
GFAP and vimentin, directly influence the ability of donor
cells to survive, migrate and integrate upon transplantation in the adult retina in vivo.
Using transgenic mice null for GFAP, vimentin, or both,
as recipients, and retinal donor cells expressing green
fluorescent protein (GFP), they systematically examined
migration and neurite outgrowth properties of the transplanted cells in vivo. From these studies, they conclude
that a lack of the non-permissive proteins, GFAP and
vimentin, contributes significantly to the success with
which donor cells integrate in an otherwise inhibitory
Update
TRENDS in Neurosciences Vol.27 No.5 May 2004
environment. Contrary to results in wild-type mice
(where transplanted neurons typically fail to survive
and integrate in the adult retina), when postnatal-day
(P)0 retinal suspensions were transplanted into
GFAP 2/2 /Vim 2/2 mice, many of the transplanted
cells were able to migrate long distances away from
the injection site, especially to the ganglion cell layer,
resulting in an increased number of re-populated
neurons. In addition, in GFAP 2/2 /Vim 2/2 mice,
donor cells displayed a marked increase in both the
number of extended neurites and the length of such
neurites.
Intriguingly, the cellular integration reported by
Kinouchi et al. appeared to be somewhat cell-type- and
layer-specific, with donor cells seemingly preferentially
integrating into the ganglion cell layer rather than
differentiating into other types of neurons, such as
amacrine or bipolar cells, or into glia. Many cells were
alive and appeared morphologically integrated into the
recipient retina six months following transplantation,
although the authors did not address whether these
cells truly differentiated into retinal ganglion cells, as
neither electrophysiological nor axonal projection analysis was performed. Similar results were obtained using
donor cells from older mice (P14– P21), which notoriously survive and integrate more poorly following
transplantation. Just as with cells from younger P0
donors, P14 –P21 donor cells were also apparently able
to integrate much more effectively into GFAP 2/2 /Vim 2/2
retinas than into wild-type retinas. It will be interesting in the future to examine the precision of differentiation of these newly integrated cells using
increasingly refined marker analysis, electrophysiology,
and investigation of whether at least a subset can
establish the correct pattern of long-distance connections to the superior colliculus.
Potential roles for GFAP and vimentin
What is it about the production or presence of the
intermediate-filament proteins GFAP and vimentin
that limits neuronal integration? Clearly, these proteins are intimately involved in reactive gliosis and the
formation of the ‘glial scar’ [7 – 10], but in what manner
is this phenomenon occurring? To become successfully
integrated into the recipient environment, a transplanted cell must be able to complete a coordinated
sequence of crucial developmental steps. It must first
survive, migrate to the correct final location, and then
differentiate appropriately. Finally, it must be able to
intercalate into the recipient environment to achieve
functional integration and long-term stability. Which of
these crucial steps is enhanced by the lack of GFAP
and vimentin in astroglia? Are GFAP 2/2 /Vim 2/2
astroglia developmentally different from their wildtype counterparts [11,12]? Are these astroglia less able
to form a glial scar, thus enhancing the ability of adultborn neurons to integrate and extend processes, in
turn enhancing their long-term survival? Limitation of
neuronal process formation by the glial scar might very
well be one of the multiple normal astroglial effects
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239
that are interfered with in the absence of GFAP and
vimentin. Interestingly, immediate (as well as longterm) survival of the transplanted cells appears to be
enhanced in this animal model. Further experiments
should consider whether GFAP and vimentin modulate
interference by astroglia with molecules involved in
neuronal survival. Alternatively, given the well-established role of astroglia in providing neighbouring
neurons with trophic support, the lack of GFAP and
vimentin might enhance the ability of astroglia to
produce and/or release such growth and neurotrophic
factors, although it is not at all clear by what means
this process would occur at the molecular level.
Another relevant issue indirectly raised by the report
of Kinouchi et al. concerns the potential compensatory
or synergistic roles of different classes of astroglial
filament proteins, because it appears that lack of
neither GFAP nor vimentin alone is capable of enabling
the robust neuronal integration that is seen when both
proteins are absent. However, these double-knockout
mice have modified expression of other cell adhesion
molecules, such as laminin and N-cadherin [13,14].
Finally, it should also be noted that the process of cell
transplantation itself might influence retinal GFAP
and/or vimentin expression, and that these changes
could in turn modulate the volume of the extracellular
space within the retina [15,16]. A clearer understanding of the precise roles these molecules play, both in
the retina and in other CNS regions, will be crucial for
the development of therapeutic approaches toward
directed CNS repair.
A fine balance
Kinouchi et al.’s experiments provide a useful paradigm by which to probe for both inhibitory and
permissive factors associated with astroglia. There is
an intimate interplay between the recipient environment and the donor cells themselves, and indeed one
can imagine that this complex interplay occurs at a
more cell-specific level, between recipient astroglia and
transplanted neurons. Just as glia exert a variety of
negative influences, including glial scarring, gliosis and
the presence of GFAP, vimentin and other repulsive
factors [7 – 9,17 – 22], astroglia also provide support for
neuronal integration and survival. These positive
influences from glial cells can occur both developmentally and in adulthood; such influences can
include, but are not limited to, the provision of trophic
support, extracellular buffering, neurotransmitter
reuptake and recycling, and cellular scaffolding for
neuronal migration or for axonal or dendritic extension
[23,24]. These seemingly contradictory roles of astroglia are thus of a complex and presumably complementary nature (Figure 1).
Neural transplantation involves an intricate
relationship between donor cells and the recipient
environment, yet the focus of the majority of transplantation studies has been on the characterization of
the donor cells themselves, rather than on the
environment into which these cells are introduced.
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TRENDS in Neurosciences Vol.27 No.5 May 2004
Trophic support
Synaptogenesis
Neurogenic ‘niche’
Permissive cues?
Progenitor?
GFAP
Vimentin
Glial scar
Gliosis
Inhibitory signals
Successfully integrated neuron
• migration
• survival
• neurite outgrowth
• connectivity/architecture
• electrophysiological function
TRENDS in Neurosciences
Figure 1. The ‘star-cross’d neuron’*: Successful integration of neurons relies on their ability to survive, migrate, mature and integrate functionally into the recipient CNS
architecture. Astroglia play complementary but seemingly contradictory roles in this process; they can provide, for example, both trophic support and inhibitory signals.
Abbreviation: GFAP, glial-fibrillary acidic protein. * With apologies to W. Shakespeare.
There is a clear need to understand the signals present
in the recipient microenvironment that affect its ability
to support neuronal differentiation, integration and/or
neurogenesis from endogenous precursors, so that the
local microenvironment in distinct pathological situations can be directed towards CNS repair [25].
However, there is a substantial lack of knowledge
regarding the molecular mechanisms involved. The
report by Kinouchi et al. provides evidence that
filament proteins commonly found in astroglia can
affect neuronal integration dramatically in the adult
retina, and demonstrate how crucially astroglia can
control neuronal fate, far beyond what is typically
thought. By highlighting this pivotal role for astroglia
in the adult CNS, Kinouchi et al. provide further
evidence for the varied, at times seemingly contradictory, and crucial roles of astroglia. This emphasizes
that work towards understanding the potentially
varied and certainly vital roles of glia in CNS repair
has only just begun.
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