**5. Injury-induced neurogenesis and its regulation by TGF-β family proteins**

We have described the role of TGF-β proteins in the regulation of neurogenesis under basal conditions. In response to various injuries, the rate of neurogenesis is increased and the fate and migration of the neural progenitors is changed. Cerebral ischemia, excitotoxicity and TBI can all promote neurogenesis in the adult DG and SVZ [88, 150-153]. After injury, the altered environment changes the basic processes of proliferation, differentiation, migration and integration. TGF-β related cytokines have the potential to regulate many of these processes. Alteration in the destination of progenitor cells means that many of the neuroblasts change their usual trajectory and migrate towards and into the lesion [154]. The cell fate of progenitor cells can be altered by the changed environment of the injured brain, in both the neurogenic niche and at the lesion site to which the progenitor cells migrate. The environment around the lesion is now very different than the normal location of these progenitors and thus further differentiation and integration occurs in an entirely unique environment [155]. Additionally, the actions of TGF-β cytokines are highly context dependent, and they can have very different effects in the injured as compared to the uninjured brain.

**Figure 2. Confocal images of the TGF-β ligands, receptors and signaling proteins in the SVZ and DG in the in‐ jured adult mice brain.** Double and triple labelled inmmunofluorescence staining for TGF-β proteins and receptors, with the following cell-type specific markers: Nestin (for undifferentiated neuronal precursors), NeuN (for mature neu‐ rons), GFAP (for progenitor and astroglial cells), DCX (for neuroblasts). The left column shows coronal sections within

14 Trends in Cell Signaling Pathways in Neuronal Fate Decision

A major component of the brain post-injury in comparison to the uninjured brain is the inflammatory response, both of local CNS cells and invading macrophages. While the majority of studies have indicated that inflammation is detrimental to neurogenesis, it is now appreciated that the effect of inflammation on neurogenesis is multifaceted [156]. Of particular importance is the response of local microglia and astrocytes in the neurogenic regions. Microglia are potent regulators of neurogenesis, and in certain contexts can powerfully inhibit the process [157]. However microglia have also been shown to pro‐ mote neurogenesis [158, 159], and studies have described differential action of acute vs. chronically activated microglia on NSC division and neurogenesis, as well as for micro‐ glia activated by different mechanisms or by different cytokines [160, 161]. As TGF-β proteins are prominent anti-inflammatory molecules [162], their actions after brain injury can regulate neurogenesis by acting directly on NSCs as well as indirectly through their effects on the glial inflammatory response [163].

**TGF-β related protein**

Noggin

BMP7

Chordin

Activin-A

Activin-A or Activin-B

Follistatin

**Animal Model**

Naïve animals

Permanent MCAO

Naïve animals

Cuprizone-induced corpus callosum demyelination

Spinal cord injury

Transient ischemia

Naïve animals

Lysolectithininduced corpus callosum demyelination

Excitotoxic hippocampal lesion

Excitotoxic hippocampal lesion

Naïve mice Transgenic

Naïve mice Transgenic

**Mode of administration**

Transgenic astrocytic overexpression

Transgenic neuronal overexpression

Intraventricular infusion

Intraventricular infusion

Overexpression by transplanted

Intraventricular infusion

Intraventricular

Intraventricular infusion

Continuous intraventricular infusion

overexpression

Continuous intraventricular infusion

overexpression

NPCs.

**Effect on cell proliferation and neurogenesis**

proliferation and generation of neuroblasts and neurons

Decreased DG cell

Increased immature oligodendrocyte generation

Promoted neuronal differentiation of SVZ precursor cells transplanted to

Decreased astrocyte and increased oligodendrocyte generation from the SVZ

Increased neuronal and oligodendroglial

differentiation of transplanted

infusion Inhibited SVZ proliferation None measured [96]

Increases new neuron survival Reduced anxiety-like

Increased SVZ proliferation and neurogenesis

Increased NPCs migrating to lesion, and increased oligodendrocyte differentiation

Decreased astrocyte and microglial inflammation, and increases neurogenesis

Increased NSC proliferation and neurogenesis.

Naïve mice ICV injection Not examined Reduced depression-

Potently inhibited neurogenesis

**Table 3.** Therapeutic application of TGF-β proteins in the normal and injured brain that affect neurogenesis.

the striatum

NPCs

**Behavioral Outcome**

Role of TGF-β Signaling in Neurogenic Regions After Brain Injury

Reduced motor

Improved motor recovery

Reduced motor

None measured [87]

http://dx.doi.org/10.5772/53941

deficits [167]

None measured [96]

None measured [115]

deficits [145]

None measured [169]

None measured [88]

behavior [91]

like behavior [170]

None measured [88]

Increased anxiety-like behavior [91]

**Reference**

17

[168]

Due to their pleiotropic actions, TGF-β superfamily proteins have been investigated as potential treatments for a variety of CNS injuries, and several studies have demonstrated potential uses for these cytokines as therapeutic molecules (see Table 3). They have also provided insights into the action of these molecules as regulators of neural stem/progenitor cell (NSPC) proliferation and differentiation, with respect to both endogenous and transplant‐ ed stem cell populations.



A major component of the brain post-injury in comparison to the uninjured brain is the inflammatory response, both of local CNS cells and invading macrophages. While the majority of studies have indicated that inflammation is detrimental to neurogenesis, it is now appreciated that the effect of inflammation on neurogenesis is multifaceted [156]. Of particular importance is the response of local microglia and astrocytes in the neurogenic regions. Microglia are potent regulators of neurogenesis, and in certain contexts can powerfully inhibit the process [157]. However microglia have also been shown to pro‐ mote neurogenesis [158, 159], and studies have described differential action of acute vs. chronically activated microglia on NSC division and neurogenesis, as well as for micro‐ glia activated by different mechanisms or by different cytokines [160, 161]. As TGF-β proteins are prominent anti-inflammatory molecules [162], their actions after brain injury can regulate neurogenesis by acting directly on NSCs as well as indirectly through their

Due to their pleiotropic actions, TGF-β superfamily proteins have been investigated as potential treatments for a variety of CNS injuries, and several studies have demonstrated potential uses for these cytokines as therapeutic molecules (see Table 3). They have also provided insights into the action of these molecules as regulators of neural stem/progenitor cell (NSPC) proliferation and differentiation, with respect to both endogenous and transplant‐

> **Effect on cell proliferation and neurogenesis**

Decreased NSC proliferation and induce the number of DCX expressing neuronal

Decreased the percentage of dividing cells which co-express

Increased NSC proliferation and neurogenesis in the SVZ

Inhibited chronic microglial activation and restored

Number of proliferating cells in the hippocampus and in the lateral ventricle wall is substantially reduced, fewer neuronal precursor cells

PSA-NCAM in the DG

neurogenesis

precursors

**Behavioral Outcome**

Reduced Neurological Severity Score deficits [164]

None measured [163]

None measured [165]

None measured [166]

None measured [81]

**Reference**

effects on the glial inflammatory response [163].

16 Trends in Cell Signaling Pathways in Neuronal Fate Decision

**Mode of administration**

spray

Intranasal aerosol

Intraventricular infusion

Adult adenoviral overexpression

Injected into the cerebrospinal fluid

Adenoviral overexpression

ed stem cell populations.

**Animal Model**

Transient ischemia

Adrenalectomy

Adrenalectomy

Prenatal LPS inflammation

Naïve animals

**TGF-β related protein**

TGFβ-1

**Table 3.** Therapeutic application of TGF-β proteins in the normal and injured brain that affect neurogenesis.

#### **5.1. TGF-β1**

TGF-β1 treatment improves the outcome in several models of injury as it is strongly neuroprotective [76, 133, 171, 172] and in certain circumstances can promote neurogenesis after injury. After middle cerebral artery occlusion (MCAO) in mice, intranasal treatment with TGF-β1 increases the number of proliferative DCX-positive neural progenitors and the number of new neurons in the SVZ and striatum, while decreasing the fraction of prolifera‐ tive cells that express GFAP [119]. After adrenalectomy, TGF-β also stimulates neurogene‐ sis. TGF-β1 expression is upregulated and is necessary for the increased rates of neurogenesis in the SVZ and DG caused by adrenalectomy [163]. In this model TGF-β mediated downre‐ gulation of microglial activation and proliferation may be partially responsible for the increased neurogenesis [163, 165]. TGF-β1 can also inhibit chronic microglial activation induced by prenatal LPS exposure, and ameliorate the LPS-mediated decrease in neurogen‐ esis [166] suggesting that the anti-inflammatory action of TGF-β participates in its proneurogenic effects. Conversely, in naïve animals intracerebroventricular infusion of TGF-β1 lowered the number of DCX-positive neuronal precursors in the neurogenic niches. This reduced level of proliferation in the TGF-β1 infused brains was strongly correlated with an increased accumulation of pSmad2 in Sox2/GFAP expressing cells of the SGZ [81]. Transgen‐ ic overexpression of TGF-β1 in naïve mice also leads to reduce neurogenesis [87]. The opposite effects of TGF-β1 in injured as compared to naïve animals illustrate the difficulty in assigning one specific role to TGF-β1 due to its context-dependent effects. Chronic inflammation, either after lesion or in neurodegenerative disease, provides a different environment for the consequences of TGF-β signaling. The anti-inflammatory actions of TGF-β can have an important role in influencing neurogenic processes, independent of direct effects on neural progenitor cells. Dysregulation of TGF-β signaling is being acknowledged as a potential source for chronic inflammation. Indeed, aberrant TGF-β signaling and consequent accumu‐ lation of activated microglia in the neurogenic regions may play an important role in the progression of Alzheimer's disease [171, 173].

**5.3. BMPs**

In the naïve rodent, BMPs usually act to suppress neurogenesis in the SVZ and DG whereas the BMP inhibitor noggin promotes it [96]. In contrast, inhibition of BMP signaling by upre‐ gulation of the BMP inhibitor chordin after lysolecithin-induced demyelination of the corpus callosum, led to redirection of SVZ precursors away from a neuronal lineage towards that of oligodendrocytes [169]. This change in differentiation potential was accompanied by a change in the migration pattern of the SVZ precursors, away from the rostral migratory stream, and towards the corpus callosum. Injury-induced changes in expression of regulatory factors often alter the normal pattern of cell differentiation and migration [176, 177]. In a different model of demyelination, cuprizone-induced upregulation of BMP-4 resulted in more SVZ precursors becoming astrocytes, with a concomitant reduction in the number of mature oligodendrocytes [115]. Intraventricular infusion of noggin in this model increased the generation of oligoden‐ drocytes from the SVZ [115] illustrating that inhibition of BMP signaling has the potential to promote remyelination in models of multiple sclerosis. The astrogliogenic potential of BMP has been demonstrated in multiple studies, where various precursors are pushed towards the astrocytic lineage [168, 178]. This is also true with transplanted neural stem cells or mesen‐ chymal stem cells, where BMPs around the implantation site push the transplanted cells towards astrocytes [179]. If these cells are being used to enhance repair after spinal cord or TBI, inhibition of BMP becomes an attractive option to promote neuronal or oligodendrocyte differentiation rather than that of astrocytes. In contrast to all these studies, one group has shown that BMP-7 has neuroprotective properties which may enhance the survival of imma‐ ture neurons [142, 180]. In one study, infusion of BMP-7 into the lateral ventricles of rats 24 hours after transient MCAO led to increased numbers of proliferating NSCs and more mature neurons generated in the SVZ while also facilitating behavioral recovery [145]. However, a different group has shown that transgenic expression of the BMP-inhibitor noggin in neurons after permanent MCAO in the mouse enhances functional recovery [167]. These conflicting data illustrate the sometimes confusing nature of the literature whereby BMP effects, similar to those of TGF-β are extremely contextual and are dependent on the exact model used. Overall, although some BMPs may have neuroprotective properties, the vast majority of the literature supports the view that BMP induction after injury is not beneficial for recovery, and that

Role of TGF-β Signaling in Neurogenic Regions After Brain Injury

http://dx.doi.org/10.5772/53941

19

inhibition of BMP signaling may have therapeutic potential.

In spite of extensive research in the field of brain injury or stroke, there is little effective treatment for these injuries [182]. Many of the neuroprotective treatments that have been successful in rodents have failed in clinical trials [183]. Harnessing the regenerative capaci‐ ty of the adult brain is one strategy for repairing and replacing injured tissue, together with enhancing neurotrophic support of existing neurons to promote survival [184, 185]. A complementary strategy also under development is transplantation of neural stem cells or committed progenitors into the lesion. However, when multipotent NSCs were implanted

**6. Future therapeutic strategies**

#### **5.2. Activin**

Recent studies have demonstrated a critical role for activin signaling as a modulator of adult neurogenesis [91] in addition to its well-established role as a neuroprotective molecule [174, 175]. After local excitotoxic injury to the hippocampus, ablating activin signaling by infusion of the activin inhibitor follistatin potently inhibits post-injury neurogenesis and exacerbates the inflammatory response of astrocytes and microglia. Conversely, infusion of activin-A facilitates neurogenesis and represses gliosis [88]. Perhaps related to its effects on neurogen‐ esis, activin can also regulate anxiety and depression-like behavior in rodents, and the activin pathway may be a useful therapeutic target for treating depression. Hippocampal infusion of activin-A or activin-B reduces measures of depression in a forced swim test, with a similar efficacy to that of the antidepressant fluoxetine [170]. Further, transgenic mice which overex‐ press activin-A, have decreased anxiety measures in spontaneous place preference tests, while mice which overexpress follistatin, display the reverse [91].

#### **5.3. BMPs**

**5.1. TGF-β1**

18 Trends in Cell Signaling Pathways in Neuronal Fate Decision

**5.2. Activin**

progression of Alzheimer's disease [171, 173].

mice which overexpress follistatin, display the reverse [91].

TGF-β1 treatment improves the outcome in several models of injury as it is strongly neuroprotective [76, 133, 171, 172] and in certain circumstances can promote neurogenesis after injury. After middle cerebral artery occlusion (MCAO) in mice, intranasal treatment with TGF-β1 increases the number of proliferative DCX-positive neural progenitors and the number of new neurons in the SVZ and striatum, while decreasing the fraction of prolifera‐ tive cells that express GFAP [119]. After adrenalectomy, TGF-β also stimulates neurogene‐ sis. TGF-β1 expression is upregulated and is necessary for the increased rates of neurogenesis in the SVZ and DG caused by adrenalectomy [163]. In this model TGF-β mediated downre‐ gulation of microglial activation and proliferation may be partially responsible for the increased neurogenesis [163, 165]. TGF-β1 can also inhibit chronic microglial activation induced by prenatal LPS exposure, and ameliorate the LPS-mediated decrease in neurogen‐ esis [166] suggesting that the anti-inflammatory action of TGF-β participates in its proneurogenic effects. Conversely, in naïve animals intracerebroventricular infusion of TGF-β1 lowered the number of DCX-positive neuronal precursors in the neurogenic niches. This reduced level of proliferation in the TGF-β1 infused brains was strongly correlated with an increased accumulation of pSmad2 in Sox2/GFAP expressing cells of the SGZ [81]. Transgen‐ ic overexpression of TGF-β1 in naïve mice also leads to reduce neurogenesis [87]. The opposite effects of TGF-β1 in injured as compared to naïve animals illustrate the difficulty in assigning one specific role to TGF-β1 due to its context-dependent effects. Chronic inflammation, either after lesion or in neurodegenerative disease, provides a different environment for the consequences of TGF-β signaling. The anti-inflammatory actions of TGF-β can have an important role in influencing neurogenic processes, independent of direct effects on neural progenitor cells. Dysregulation of TGF-β signaling is being acknowledged as a potential source for chronic inflammation. Indeed, aberrant TGF-β signaling and consequent accumu‐ lation of activated microglia in the neurogenic regions may play an important role in the

Recent studies have demonstrated a critical role for activin signaling as a modulator of adult neurogenesis [91] in addition to its well-established role as a neuroprotective molecule [174, 175]. After local excitotoxic injury to the hippocampus, ablating activin signaling by infusion of the activin inhibitor follistatin potently inhibits post-injury neurogenesis and exacerbates the inflammatory response of astrocytes and microglia. Conversely, infusion of activin-A facilitates neurogenesis and represses gliosis [88]. Perhaps related to its effects on neurogen‐ esis, activin can also regulate anxiety and depression-like behavior in rodents, and the activin pathway may be a useful therapeutic target for treating depression. Hippocampal infusion of activin-A or activin-B reduces measures of depression in a forced swim test, with a similar efficacy to that of the antidepressant fluoxetine [170]. Further, transgenic mice which overex‐ press activin-A, have decreased anxiety measures in spontaneous place preference tests, while

In the naïve rodent, BMPs usually act to suppress neurogenesis in the SVZ and DG whereas the BMP inhibitor noggin promotes it [96]. In contrast, inhibition of BMP signaling by upre‐ gulation of the BMP inhibitor chordin after lysolecithin-induced demyelination of the corpus callosum, led to redirection of SVZ precursors away from a neuronal lineage towards that of oligodendrocytes [169]. This change in differentiation potential was accompanied by a change in the migration pattern of the SVZ precursors, away from the rostral migratory stream, and towards the corpus callosum. Injury-induced changes in expression of regulatory factors often alter the normal pattern of cell differentiation and migration [176, 177]. In a different model of demyelination, cuprizone-induced upregulation of BMP-4 resulted in more SVZ precursors becoming astrocytes, with a concomitant reduction in the number of mature oligodendrocytes [115]. Intraventricular infusion of noggin in this model increased the generation of oligoden‐ drocytes from the SVZ [115] illustrating that inhibition of BMP signaling has the potential to promote remyelination in models of multiple sclerosis. The astrogliogenic potential of BMP has been demonstrated in multiple studies, where various precursors are pushed towards the astrocytic lineage [168, 178]. This is also true with transplanted neural stem cells or mesen‐ chymal stem cells, where BMPs around the implantation site push the transplanted cells towards astrocytes [179]. If these cells are being used to enhance repair after spinal cord or TBI, inhibition of BMP becomes an attractive option to promote neuronal or oligodendrocyte differentiation rather than that of astrocytes. In contrast to all these studies, one group has shown that BMP-7 has neuroprotective properties which may enhance the survival of imma‐ ture neurons [142, 180]. In one study, infusion of BMP-7 into the lateral ventricles of rats 24 hours after transient MCAO led to increased numbers of proliferating NSCs and more mature neurons generated in the SVZ while also facilitating behavioral recovery [145]. However, a different group has shown that transgenic expression of the BMP-inhibitor noggin in neurons after permanent MCAO in the mouse enhances functional recovery [167]. These conflicting data illustrate the sometimes confusing nature of the literature whereby BMP effects, similar to those of TGF-β are extremely contextual and are dependent on the exact model used. Overall, although some BMPs may have neuroprotective properties, the vast majority of the literature supports the view that BMP induction after injury is not beneficial for recovery, and that inhibition of BMP signaling may have therapeutic potential.

#### **6. Future therapeutic strategies**

In spite of extensive research in the field of brain injury or stroke, there is little effective treatment for these injuries [182]. Many of the neuroprotective treatments that have been successful in rodents have failed in clinical trials [183]. Harnessing the regenerative capaci‐ ty of the adult brain is one strategy for repairing and replacing injured tissue, together with enhancing neurotrophic support of existing neurons to promote survival [184, 185]. A complementary strategy also under development is transplantation of neural stem cells or committed progenitors into the lesion. However, when multipotent NSCs were implanted

directly into non-neurogenic regions in the injured brain, such as in the cortex or striatum, they failed to generate neurons but instead generated glial cells [186, 187]. Endogenous neural progenitors also are limited in their differentiation potential, presumably because the postlesion environment is one that supports glial differentiation in preference to that of neu‐ rons [188]. As TGF-β family members can promote astrogliogenesis [189, 190], it would seem that in some circumstances, inhibition of specific cytokine signals would increase neuronal differentiation. A further consideration for repair and neuronal survival is promotion of oligodendrocyte survival and differentiation, since remyelination is critical to continued survival and function of many neurons. Inhibition of BMP action through infusion of noggin can promote oligodendrocyte differentiation after demyelination [115]. Inflammation after injury is yet one more factor that alters the environment for regeneration. Although often thought of as a short-lived phenomenon, there can be longer lasting inflammatory changes that persist months after injury [191]. One of the major problems with development of members of the TGF-β superfamily or their inhibitors for therapeutic use are the pleiotrop‐ ic nature of their effects. Thus TGF-β1 itself is neuroprotective and anti-inflammatory, which should promote recovery, but it inhibits proliferation of precursors, and also promotes development of the glial scar through upregulation of many extracellular matrix mole‐

Role of TGF-β Signaling in Neurogenic Regions After Brain Injury

http://dx.doi.org/10.5772/53941

21

These cytokines act in a context dependent and concentration dependent manner, which adds an additional layer of complexity. To develop better therapeutic strategies we need a deeper understanding of the mechanisms through which the many actions of each cytokine are mediated. We may then be able to target specific molecules in the downstream signaling pathways, to avoid the pleiotropic effects that are emblematic of the activity of this cytokine

This study was supported by grant from the Center for Neuroscience and Regenerative Medicine (CNRM). SV is supported by a CNRM postdoctoral fellowship. The opinions and assertions contained herein are the private opinions of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences or the US

Department of Pharmacology and Center for Neuroscience and Regenerative Medicine, Uni‐

cules, and through enhancing the migration of astrocytes [128, 192].

family.

**Acknowledgements**

Department of Defense.

Sonia Villapol, Trevor T. Logan and Aviva J. Symes

formed Services University of the Health Sciences, Bethesda, MD, USA

**Author details**

**Figure 3. Modulation of neurogenesis and gliogenesis after adult brain injury by members of the TGF-β cyto‐ kine superfamily.** In the top panel, the dentate gyrus (DG) in the hippocampus and subventricular zone (SVZ) of the lateral ventricles are shown after damage to the cerebral cortex. Note the proliferation and migration of cells from the SVZ and DG towards the infarcted area (blue arrows). Red dots represent proliferating and migrating neural stem cells and progenitors cells (NSPCs) located in these neurogenic regions. In the bottom panel, the role of TGF-β proteins at different stages of neurogenesis or gliogenesis after adult brain injury is illustrated. Proliferation, migration or differ‐ entiation are induced or inhibited by growth factors, such as: TGF-β, BMPs proteins, Activin, Follistatin or Noggin. After injury to the brain, TGF-β1 can increase proliferation of NSPCs and induce the differentiation of neuroblasts into neu‐ rons within the SVZ, [119]. BMP7 can induce neural stem cell proliferation, neuronal migration and differentiation [145]; other BMPs proteins (BMP2-7) also can stimulate neuronal migration [94]. The BMP inhibitor proteins noggin and chordin promote NSPC migration and oligodendrocyte proliferation and differentiation, while decreasing astro‐ cyte proliferation [115, 169]. After injury to the brain, within the DG TGF-β1 can reduce the proliferation of immature neurons while increasing neuronal migration and differentiation [165, 166]. BMP7 can enhance NSPC proliferation and neuronal differentiation [96, 145]. Noggin can also increase NSPC proliferation [169]. Generally, BMPs can in‐ crease astroglial differentiation and inhibit oligodendrocyte generation, and the BMP inhibitors Chordin and Noggin can facilitate oligodendrocyte differentiation and proliferation [181]. Activin can induce NSPCs proliferation, and de‐ crease microglial and astroglial proliferation. The activin antagonist, follistatin, reduces proliferating NSPCs and mi‐ grating neuroblasts [88]. In summary, the proliferation, migration and differentiation of cells in the SVZ and the DG may be influenced by the spatial and temporal expression profile of these TGF-β proteins after brain injury.

directly into non-neurogenic regions in the injured brain, such as in the cortex or striatum, they failed to generate neurons but instead generated glial cells [186, 187]. Endogenous neural progenitors also are limited in their differentiation potential, presumably because the postlesion environment is one that supports glial differentiation in preference to that of neu‐ rons [188]. As TGF-β family members can promote astrogliogenesis [189, 190], it would seem that in some circumstances, inhibition of specific cytokine signals would increase neuronal differentiation. A further consideration for repair and neuronal survival is promotion of oligodendrocyte survival and differentiation, since remyelination is critical to continued survival and function of many neurons. Inhibition of BMP action through infusion of noggin can promote oligodendrocyte differentiation after demyelination [115]. Inflammation after injury is yet one more factor that alters the environment for regeneration. Although often thought of as a short-lived phenomenon, there can be longer lasting inflammatory changes that persist months after injury [191]. One of the major problems with development of members of the TGF-β superfamily or their inhibitors for therapeutic use are the pleiotrop‐ ic nature of their effects. Thus TGF-β1 itself is neuroprotective and anti-inflammatory, which should promote recovery, but it inhibits proliferation of precursors, and also promotes development of the glial scar through upregulation of many extracellular matrix mole‐ cules, and through enhancing the migration of astrocytes [128, 192].

These cytokines act in a context dependent and concentration dependent manner, which adds an additional layer of complexity. To develop better therapeutic strategies we need a deeper understanding of the mechanisms through which the many actions of each cytokine are mediated. We may then be able to target specific molecules in the downstream signaling pathways, to avoid the pleiotropic effects that are emblematic of the activity of this cytokine family.
