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Cellular and molecular mechanisms of neural repair after stroke Making waves.

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NEUROLOGICAL PROGRESS
Cellular and Molecular Mechanisms of
Neural Repair after Stroke: Making Waves
S. Thomas Carmichael, MD, PhD
Stroke is associated with a limited degree of functional recovery. Imaging studies in humans have shown that reorganization in periinfarct and connected cortical areas most closely correlates with functional recovery after stroke. On a
cellular level, two major regenerative events occur in periinfarct cortex: axons sprout new connections and establish novel
projection patterns, and newly born immature neurons migrate into periinfarct cortex. Stroke induces a unique microenvironment for axonal sprouting in periinfarct cortex, in which growth-inhibitory molecules are reduced for 1 month
after the infarct. During this period, neurons activate growth-promoting genes in successive waves. Neurogenesis also
occurs through waves of migration of immature neurons from their origin in the subventricular zone into periinfarct
cortex. This migration is mediated, in part, by the cytokine erythropoietin. These data indicate that the cellular environment after stroke is far from one of just death and destruction, but rather involves a longer evolving process of
neuronal regeneration. Poststroke neuronal regeneration is characterized by waves of specific cellular and molecular
events. Manipulating these waves of regeneration may provide for novel therapies that will improve recovery after stroke.
Ann Neurol 2006;59:735–742
Stroke is the leading cause of adult disability. Sixty percent of survivors have disabilities in arm or leg use, and
up to one-third need placement in a nursing home or
assisted living environment. This translates to more
than $30 billion in annual care for stroke survivors—
well more than half of the annual cost of stroke.1,2 Recently, studies have shown that after stroke existing
neurons can sprout new connections and new neurons
can migrate to areas of injury. Axonal sprouting and
neurogenesis after stroke occur in periinfarct tissue, a
region of cortical remapping that closely correlates with
recovery after stroke in humans. This review focuses on
the cellular and molecular mechanisms of axonal
sprouting and neurogenesis in periinfarct cortex, and
how an understanding of these two processes might
lead to novel therapies for neural repair after stroke.
Patterns of Recovery in the Human Brain after
Stroke: Periinfarct Cortex
Stroke reorganizes cognitive maps in cortex in patterns
that correlate with functional recovery. Subcortical
stroke first induces a bilateral cortical activation to sensory or motor stimulation of the affected limb. This
bilateral pattern then becomes more restricted as patients recover, to a reorganized and expanded sensorimotor activation in the cortex contralateral to the affected limb (the side of the stroke) and an increase in
From the Department of Neurology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA.
Received Feb 21, 2006. Accepted for publication Feb 25, 2006.
Published online Apr 24, 2006 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20845
activity in the connected regions of supplementary motor and premotor areas on this same side.3–5 In crosssectional imaging studies of patients with good functional recovery, cortical activation occurs in an
expanded or altered representation in sensorimotor areas contralateral to the affected limb, and this “ipsilesional” activation is most closely correlated with good
recovery. Cortical activity in the cortex opposite to the
stroke correlates with reduced functional recovery.6 – 8
These studies are limited by the types of sensory or
motor activation paradigms that can be performed during scanning; other studies suggest that alternative recovery patterns may be present.9 However, similar data
have been obtained after functional recovery from
hemispatial neglect10 and aphasia,11,12 in which recovery is associated with a reorganization of cortical activity over time in a network of areas ipsilateral to the
lesion. Similarly, transcranial magnetic stimulation
mapping studies indicate that stroke induces new
movement representations in periinfarct motor cortex,
which correlate with functional recovery.13,14 Focal inactivation with transcranial magnetic stimulation in recovered patients in cortex adjacent or ipsilateral to the
stroke produces deficits in movement of the affected
limb, but inactivation of the cortex contralateral to the
stroke does not alter limb movement.15,16 These findings from multiple brain activation paradigms indicate
Address correspondence to Dr Carmichael, Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building, 635 Charles Young Drive South, Los Angeles, CA
90095. E-mail: scarmichael@mednet.ucla.edu
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
735
that functional recovery after stroke occurs largely
through an evolving reorganization of cortical activity
within cortex adjacent to, or connected with, the stroke
site, and not through the development of novel contralateral cortical activation patterns.
Axonal Sprouting in Periinfarct Cortex
Adult cortex responds to injury or deafferentation with
axonal sprouting. Peripheral nerve injury or altered
limb use produce substantial axonal sprouting in sensory cortex in nonhuman primates.17 Retinal lesions
induce neurons in cortex that borders the deafferented
area to sprout new projections into this area.18 Cerebellar lesions induce sprouting from primary sensory
cortex into motor cortex.19 These studies indicate that
axonal sprouting in cortex after peripheral deafferentation occurs in different species, over long distances,
and between functionally different cortical areas.
Axonal sprouting occurs in periinfarct and connected
cortical areas after stroke. Stroke induces GAP43, a
growth cone phosphoprotein that is highly linked to
axonal sprouting,20 in human periinfarct cortex21 and
in periinfarct cortex in experimental stroke models.22,23
GAP43 messenger RNA and protein are increased
from 3 days to 1 month after stroke,21–23 followed by
increases in a marker for synapses within the same periinfarct region at later time points.22 This progression
from an increase in a growth cone molecule to increases in a marker for synapses suggested a progression
toward axonal sprouting in periinfarct cortex. Axonal
sprouting was directly demonstrated after stroke using
detailed neuroanatomical mapping of cortical connections in control and poststroke brains. Stroke induces
neurons in cortex both near the infarct and several millimeters away to form new connections. In the rodent,
this poststroke axonal sprouting is robust and remaps
the primary sensory cortex.24 In nonhuman primates,
poststroke axonal sprouting extends new connections
from premotor cortex to primary sensory cortex, in
some cases, over distances of up to 1cm.25 The pattern
of poststroke axonal sprouting in experimental animals
resembles the pattern of cortical remapping in human
stroke imaging studies: Axonal sprouting produces an
altered and expanded primary sensory map, and new
connections are formed between periinfarct cortex and
premotor, motor, and somatosensory cortical areas.
Stroke Induces a Permissive Environment for
Axonal Sprouting
The adult brain is normally inhibitory to axonal
sprouting. Axonal growth inhibition is mediated
through three general classes of proteins: myelinassociated proteins (NogoA, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein), extracellular matrix proteins (tenascin and chondroitin sulfate
proteoglycans), and developmentally associated growth
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cone inhibitors (such as molecules of the ephrin and
semaphorin classes).26 After injury to the central nervous system (CNS), many of these molecules are induced near the injury site. This reexpression of axonal
growth inhibitors has been particularly well studied in
spinal cord injury, where trauma induces chondroitin
sulfate proteoglycans, NogoA, ephrin B/EphB class
members, and semaphorin IIIa in the region of glial
scar.27–31 The pattern of growth-inhibitory protein expression in the brain also has been studied extensively
after brain trauma. Brain injury from stab wounds or
aspiration of tissue induces chondroitin sulfate proteoglycans, NogoA, and semaphorin IIIa in the region of
glial scar and its vicinity.27,30,32 These data have suggested that injury to the brain resembles injury to the
spinal cord in broadly inducing growth-inhibitory molecules in a gradient that extends from the injury site
into surrounding tissue. However, brain trauma is not
stroke. The mechanisms of injury in brain trauma differ substantially from those in stroke, especially regarding the dynamics and distribution of inflammation, apoptotic cell death, and reperfusion injury/free radical
damage.33–36 It is not surprising, therefore, that the degree of axonal sprouting differs markedly between
brain trauma and stroke. Stab wounds or aspiration injury to the brain does not induce a significant axonal
sprouting response,37– 40 whereas ischemic injury induces a substantial local and long-distance axonal
sprouting response.24,25,37,40 The tissue environment
that is induced by stroke differs from that seen after
brain trauma in containing a region that is permissive
for axonal sprouting.
Axonal sprouting in periinfarct cortex takes place
within a favorable environment that is adjacent to, and
larger than, the glial scar. Stroke induces gliosis in a
region of apoptotic cell death that closely borders the
infarct, extending several hundred microns into periinfarct cortex in the rat.41,42 Within this region of glial
scar, stroke induces the growth-inhibitory chondroitin
sulfate proteoglycans,23,43 the semaphorin IIIa receptor
neuropilin 1,44 and myelin-associated glycoprotein.45
Importantly, stroke also induces growth-promoting
proteins in this region of glial scar, including GAP43,
CAP23, MARCKS, and small proline repeat rich protein 1 (SPRR1)22,23,46,47 (Fig 1). Thus, the glial scar
after stroke is a narrow region that closely borders the
infarct and contains increased expression levels of both
growth-promoting and growth-inhibitory molecules.23
In contrast, a large region of periinfarct cortex that lies
just outside of the glial scar has reduced levels of
growth-inhibitory molecules. After stroke, chondroitin
sulfate proteoglycans, such as aggrecan, phosphacan,
and versican, are actually reduced in this region of periinfarct cortex23 (see Fig 1). These chondroitin sulfate
proteoglycans normally form perineuronal nets, which
encase both pyramidal and nonpyramidal neurons in
Fig 1. Growth-associated gene expression in periinfarct cortex after stroke. The schematic (top) shows the location of photomicrographs in A through J. (A–D) Aggrecan and versican are expressed in perineuronal nets in control cortex (A, C). Seven days after
stroke (B, D), aggrecan and versican expression in perineuronal nets is markedly reduced, and these two proteins are expressed
densely within the glial scar that borders the infarct (asterisks). (E–J) In situ hybridization for the growth-promoting genes GAP43,
CAP23, and small proline repeat rich protein 1 (SPRR1). The bright signal corresponds to messenger RNA expression level within
cells in cortex. (E, G, I) Control, nonstroke cortex. (F, H, J) Periinfarct cortex at 7 days after stroke. Note that there is intense
upregulation of the expression for these three growth-promoting genes in the same region and time points as for the reduction in the
growth-inhibitory aggrecan and versican proteins. Data are modified from Carmichael and colleagues.23 Scale bars ⫽ 100␮M.
adult cortex.48 After stroke, the chondroitin sulfate
proteoglycan perineuronal nests are reduced in periinfarct cortex.23,43 The reduction in a major class of
growth-inhibitory proteins is time-locked to an increase in growth-promoting molecules.23 Thus, stroke
induces a glial scar, in which both growth-promoting
and growth-inhibitory molecules are upregulated, and a
growth-permissive zone, in which growth-promoting
molecules are induced and growth-inhibitory molecules
are reduced. This growth-permissive zone corresponds
to the region of poststroke axonal sprouting.23,24
Molecular Growth-Promoting Programs for
Axonal Sprouting
Poststroke axonal sprouting means that fully differentiated adult cortical neurons must engage a neuronal
growth program: elaborate a growth cone, extend an
axon, and form new connections. The genes involved
in axonal growth have been studied in the successful
neuronal regeneration that occurs in the peripheral nervous system after injury and in the initial phases of
axonal sprouting during brain development.49 –52 Axonal sprouting requires a network of molecules that
link membrane-signaling events to growth cone phosphorylation cascades, cytoskeletal rearrangement, and
new gene transcription. These genes are induced at
specific time points in the axonal sprouting process in
peripheral nerve regeneration or brain development,
and they allow growing axons to sense the local environment and modify their cytoskeleton for directed extension.49 –54 Axonal sprouting after stroke also
progresses through specific biological time points. A
trigger phase is present 1 to 3 days after stroke, in
which rhythmic and synchronized neuronal discharges
Carmichael: Neural Repair after Stroke
737
induce axonal sprouting.40 Seven and 14 days after the
lesion are initiation and maintenance phases of the
sprouting response in stroke and other CNS lesions.22,56,57 Twenty-eight days after stroke is a time
period in which axonal sprouting has formed new patterns of connections that can be detected anatomically.24
These time points establish trigger, initiation, maintenance, and maturation phases in poststroke axonal
sprouting.
Stroke induces neuronal growth-promoting genes in
sequential waves after the infarct that correspond to the
biological time points in the sprouting response. These
waves can be categorized as an early response, an early/
sustained response, a middle response, and a late response.23 In the early response, SPRR1 is induced 3 to
7 days after stroke. Genes for the growth cone lipid
raft proteins GAP43, CAP23, and MARCKS and the
transcription factor c-Jun are induced at 3 days and
persist for the duration of the sprouting response. The
cell adhesion molecule L1, cyclin-dependent kinase inhibitor p21/waf1, and embryonic tubulin isoform T␣1
tubulin are induced at middle phases of the sprouting
response. The cytoskeletal reorganizing genes SCG10
and SCLIP are induced late, during the maturation
phase of the sprouting response. Overall, this pattern
of neuronal growth-promoting gene expression in cortex after stroke is unique compared with neuronal development, peripheral nervous system regeneration,
and nonstroke CNS lesions. Genes such as SCG10,
SCLIP, stathmin, and Rb3, which are important in
growth cone motility and responsiveness to guidance
cues53–55 and are induced early in neuronal growth
phases in other model systems after injury,58 – 60 are induced late in the sprouting response or are repressed
after stroke. L1, a member of the immunoglobulin superfamily of cell adhesion molecules that is expressed
throughout periods of axonal sprouting during development and regeneration,61– 63 is only transiently expressed in middle phases of poststroke axonal sprouting. These differences between the molecular profile of
axonal sprouting after stroke and the molecular profiles
of axonal sprouting in the peripheral nervous system
and developing nervous system have begun to identify
specific molecular targets that may account for the relative failure of regeneration in the adult brain after
ischemic injury.
Axonal sprouting after stroke requires not only the
induction of a growth-promoting program within periinfarct neurons, but also a reduction in the growthinhibitory environment. This principle has clearly
emerged from studies in other forms of CNS injury. In
spinal cord injury, a reduction in the myelin inhibitor
Nogo alone is insufficient to promote axonal regeneration.64,65 Injury to the optic nerve induces a significant axonal sprouting only with both a reduction in
Nogo levels and an induction in a growth-promoting
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program.66 In stroke, gene expression profiling shows
that the induction of the unique poststroke neuronal
growth-promoting program occurs during a window of
time in which many growth-inhibitory molecules are
not yet activated. Messenger RNA levels for the chondroitin sulfate proteoglycans aggrecan, phosphacan,
and versican are induced late after stroke, that is, after
the early, early/sustained, and middle phases of growthpromoting genes. This late induction of chondroitin
sulfate proteoglycan genes occurs over the same interval
in which chondroitin sulfate proteoglycan proteins are
removed in the region of axonal sprouting in periinfarct cortex (see earlier). Thus, both the molecular and
cellular data support the idea that this 2- to 3-week
poststroke interval is a window for axonal sprouting:
neuronal growth-promoting genes are induced, growthinhibitory proteins are removed, and many growthinhibitory genes are not yet induced.
A small number of growth-inhibitory molecules are
induced during this axonal sprouting window. Stroke
induces a wave of expression of ephrin A5, semaphorin
IIIa and its receptor neuropilin 1, and the chondroitin
sulfate proteoglycan neurocan during the initial expression peaks of the neuronal growth-promoting
genes.23,67 Ephrin A5 is a classic axonal growth inhibitor in the developing sensorimotor cortex.68 Neurons
express neuropilin 1, and elements of the CNS scar
express its ligand, semaphorin IIIa.27 With both the
inhibitory ligand and the receptor induced in periinfarct cortex, the semaphorin system is in a position to
mediate direct signaling between sprouting neurons
and the local extracellular environment. As the periinfarct cortex begins activating sequential waves of
growth-promoting genes during the initial 2- to 3-week
window after stroke, ephrin A5, neurocan, and semaphorin IIIa/neuropilin 1 are induced and in a position
to meet growing axons.
Poststroke Neurogenesis
Stroke signals to the sites of neural stem cells within
the brain, to induce the migration of newly born immature neurons (neuroblasts) into areas of ischemic
damage.69,70 In the mouse, thousands of neuroblasts
migrate long distances from their origin near the ventricles to periinfarct cortex.71 Labeling a cohort of these
cells with the thymidine analog bromodeoxyuridine allows a “tagging experiment”—neuroblasts that are born
at the same time can be followed in sequential periods
after the stroke. Tagged neuroblasts migrate from the
subventricular zone (SVZ) in waves that extend over
several days. They occupy positions around the infarct,
but the successive waves do not increase the total number of neuroblasts that are present in this region (Fig
2). This appears to be because some of the newly born
neuroblasts die within days of their arrival.71,72 Thus,
poststroke neurogenesis is a dynamic process, with
Fig 2. Erythropoietin (EPO) system in poststroke neurogenesis. (A) Schematic diagram of coronal section through mouse brain after
stroke. Boxes indicate position of photomicrographs of corresponding panels. (B) Stereological quantification of doublecortin (DCX)positive cells in cortex after stroke. The interior columns within the day 5 and 7 bars indicate the percentage of doublecortin cells that
are labeled by bromodeoxyuridine (BrdU) administration on days 1 to 3 after stroke. These doublecortin/BrdU double-labeled cells represent one cohort of neuroblasts that are all born on days 1 to 3 after stroke. These double-labeled cells progressively accumulate in control animals after stroke. In animals with a knock-down in the erythropoietin receptor (EPOR), this cohort of neuroblast initially migrates to periinfarct cortex normally (yellow bar in day 5), but then fails to migrate to cortex by day 7 compared with control (yellow
bar vs red bar in day 7). #p ⬍ 0.0001 versus day 3 and control Mut/Con; ˆp ⬍ 0.02 versus Mut day 7; *p ⬍ 0.0002 versus Mut
day 7; @p ⬍ 0.02 versus day 3 Mut/Con and nonstroke. Modified from Tsai and colleagues.71 (C) Doublecortin (green) and EPOR
(red) staining in subventricular zone (SVZ) after 7 days after stroke. Doublecortin staining recognized migrating neuroblasts after
stroke.71 Colocalization of both signals is seen in overlay images in yellow. (D–F) DCX and EPOR staining in subcortical white matter
7 days after stroke. Note that all commercially available EPOR antibodies stain EPOR, as well as other antigens80; thus, this staining
must be interpreted as showing the presence of EPOR and possibly other antigens. (G, H) EPO expression in control (G) and 7 days
after stroke (H). Note that EPO is induced in white matter (wm) after stroke in close proximity to migrating neuroblasts. (I) Summary of axonal sprouting and neuroblast migration after stroke. Bar ⫽ 100␮M.
Carmichael: Neural Repair after Stroke 739
waves of migration of newly born neuroblasts, and
waves of cell death in these recently arrived neuroblasts.
Stroke must initiate molecular signals that recruit
migrating neuroblasts to areas of injury. One of the
signals that promotes neuroblast migration after stroke
is the cytokine erythropoietin (EPO). EPO is induced
near the infarct after stroke73,74 (see Fig 2) and is under the control of the hypoxia-inducible factor 1 transcription factor, an early molecular signal after
stroke.73,74 In vitro evidence suggests that EPO promotes neuronal differentiation of neural stem cells.75,76
Pharmacological doses of EPO promote cell division
and increased neuronal progenitor cells in the SVZ after stroke.77 Using a conditional knock-out of the EPO
receptor (EPOR), researchers recently showed that
EPO functions in the normal brain to promote neural
stem cell proliferation in the SVZ and to promote neuroblast migration to periinfarct cortex after stroke.71 In
these studies, tagging experiments of migrating neuroblasts (noted earlier) were combined with knock-down
of the EPOR in neurons and astrocytes, to show that
EPO promotes the continued migration of neuroblasts
to areas of injury after stroke. When EPOR is knocked
down, only the initial wave of neuroblast migration
normally takes place. Subsequent waves of migration
are significantly smaller (see Fig 2). A conceptual
model utilizing these data and previous studies suggests
that stroke activates hypoxia-inducible factor 1 in periinfarct cortex,78 which induces endogenous EPO production around the infarct. Neuroblasts respond to this
ligand with their EPOR, and this interaction promotes
neuroblast migration to periinfarct cortex. EPO applied
pharmacologically also induces angiogenesis near the
infarct, with subsequent vascular production of growth
factors that stimulate neurogenesis.77 There are many
gaps in this framework of poststroke neurogenesis, such
as the identity of the signals that initiate poststroke
neurogenesis and the cellular microenvironment near
the stroke that fosters neuroblast survival or death.
Conclusions
Functional recovery after stroke in humans correlates
with remapping of cognitive operations in periinfarct
cortex and connected cortical areas. Within these regions, axons sprout new connections and newly born
neuroblasts migrate into areas of damage. Molecular
and cellular studies of poststroke axonal sprouting and
neurogenesis identify unique regeneration programs
within periinfarct cortex. These programs occur as
waves of growth-promoting genes and migrating neuroblasts in unique tissue microenvironments of reduced
inhibitory molecules and induced promigratory cytokines.
In one of the first California metaphors of surfing as
Life, Eugene Burdick79 describes a group of surfers
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who waited only to catch the largest wave of the day,
the ninth wave of the ninth set. Smaller waves were
mere distractions. On the beach and later in life, riding
the ninth wave made the effort complete.79 There are
many gaps in the data on regeneration after stroke,
such as the exact relationship of axonal sprouting and
neurogenesis to behavioral recovery and the identification of the key control points or master switches that
influence these processes. However, with continued
study these gaps will be filled, and the function of the
genes that ultimately complete neuronal regeneration
after stroke will be determined. We will in short order
identify the ninth wave of neural repair. However, the
endogenous mechanisms of neural repair lead to only a
limited functional recovery. To truly improve recovery
after stroke, we will have to apply the molecular principles of neural repair toward novel regenerative therapies
after stroke. We will have to make waves of our own.
This work was supported by the NIH (National Institute of Neurological Disorders and Stroke, 1R01 NS45729), American Heart
Association (0555013Y), and a Distinguished Scholar Award from
the Larry L. Hillblom Foundation.
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