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Contents lists available at ScienceDirect

The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel

Review

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Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies夽

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Tobias D. Merson a,b,∗ , James A. Bourne c,∗∗

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Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC 3010, Australia Melbourne Neuroscience Institute, The University of Melbourne, Parkville, VIC 3010, Australia Australian Regenerative Medicine Institute, Monash University, Building 75, Level 1 North STRIP 1, Clayton, VIC 3800, Australia

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a r t i c l e

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Article history: Received 10 June 2014 Received in revised form 18 July 2014 Accepted 4 August 2014 Available online xxx

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Keywords: Stroke Neural stem cells Cell proliferation Brain repair Cell signalling

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Contents

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Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischaemic lesion rapidly die and other neuronal populations in the ischaemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischaemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischaemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischaemia and are dissecting the functional importance of this regenerative mechanism following brain injury. This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation. © 2014 Published by Elsevier Ltd.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebral ischaemic injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurogenic niches of the adult central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischaemia-responsive NPCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Ischaemia-responsive NPCs within adult neurogenic zones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Ischaemia-responsive NPCs residing in the neocortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Vascular remodelling & neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Relevance of ischaemia-induced neurogenesis to functional recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Trophic function of NPCs in promoting cell survival and/or synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Hormonal regulation of neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Inflammatory regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Cell signalling molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. TGF-alpha . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. VEGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. EPO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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夽 This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation. ∗ Corresponding author at: Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC 3010, Australia. Tel.: +61 3 90356535; fax: +61 3 86779826. ∗∗ Corresponding author. Tel.: +61 3 99029622; fax: +61 3 99052766. E-mail addresses: [email protected] (T.D. Merson), [email protected], [email protected] (J.A. Bourne). http://dx.doi.org/10.1016/j.biocel.2014.08.003 1357-2725/© 2014 Published by Elsevier Ltd.

Please cite this article in press as: Merson TD, Bourne JA. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.003

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10.4. LNK adapter protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.5. CNTF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.6. Notch signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.7. Shh signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.8. FGF-2 and EGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.9. Growth hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.10. GDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.11. Neurotrophic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.12. Ephrin-B3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.13. ERK signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetic modifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future studies and clinical translation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Cerebral ischaemic injury is the most common form of stroke and accounts for a major percentage of neurological disease worldwide (Johnston et al., 2009; Feigin et al., 2014). At present, there is no reparative treatment and patients can experience a permanent loss of brain function. Approaches to reduce the burden of disease in patients who have suffered a stroke seek to limit and reverse neurological damage by reducing CNS injury and promoting neural regeneration. The normal course of disease in stoke patients includes an acute ischaemic period in which focal areas subject to ischaemic injury are vulnerable to cell death. In the subacute phase, tissue adjacent to the ischaemic core known as the ischaemic penumbra is vulnerable to further injury. A number of processes contribute to recovery following ischaemia including neuroplasticity, angiogenesis and neurogenesis. The role that neuroplasticity and angiogenesis play in mediating recovery following stroke have been recently reviewed (Ergul et al., 2012; Hermann and Chopp, 2012). Understanding the cellular and molecular processes that underlie post-ischaemic neurogenesis are important to establish the extent to which this contributes to neural regeneration after stroke and whether interventions can be developed to potentiate neural regeneration in stroke patients.

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Cerebral ischaemic injury is a pathological event caused by temporary or permanent occlusion/blockage of vascular structures within the CNS. Focal (stroke) and global (e.g. cardiac arrest) cerebral ischaemia arise from a transient or permanent impairment of blood supply to the brain, causing a local or generalised oxygen and glucose deprivation, respectively. As a consequence, vast numbers of neurons in the brain rapidly die due to the induction of complex pathological processes initiated by excessive glutamate release which is excitotoxic (reviewed by Broughton et al., 2009). The resultant overproduction of free radicals, which cause local and acute tissue injury, is followed by an inflammatory reaction marked by the activation of local microglial cells and the infiltration of peripheral leukocytes. The acute inflammation and oxidative stress that accompany early stages of stroke can result in the activation of detrimental transcription factors (e.g. nuclear factor kappa-B (NF-␬B)) and disruption the blood-brain barrier (BBB), a physical barrier within the brain providing protection and regulation of homeostasis. The prevalence of ischaemic stroke in the community has prompted the development of animal models in various species to aid in the investigation of ischaemic and reperfusion injuries. The most common model is the middle cerebral artery occlusion (MCAO) in which the artery is either transiently or permanently occluded via ligation or internal physical obstruction (Tamura et al.,

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1981). An alternative approach involves the injection of endothelin1 next to blood vessels to induce transient vasoconstriction to block vascular flow, which can be applied to various brain regions for a more focal injury (Teo et al., 2012). Another less commonly used method to induce focal ischaemia is Rose bengal cerebrocortical photothrombotic infarction (Watson et al., 1985). The regions of the brain that are affected by ischaemic stroke depend considerably on the animal model and experimental paradigm utilised, which has led to much debate and potentially contributed to significant failures in translation of research findings. To this end, there still remain very few treatment options for stroke and as such there is a pressing need to realise the potential of cellular and molecular approaches that may augment repair following such an injury. In this regard, there is considerable interest in understanding how the neurogenic niches in the adult mammalian brain are influenced by cerebral ischaemic injury and whether these responses could be optimised to provide therapeutic benefit. 3. Neurogenic niches of the adult central nervous system Most of our current understanding of adult neural stem/progenitor cell biology and the mechanics of adult neurogenesis is based upon experiments conducted using rodent models. Neurogenesis has been conclusively demonstrated to persist in two germinal niches in the adult rodent central nervous system (CNS), namely the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (reviewed by Ming and Song, 2011). Neural stem cells located in these regions are relatively quiescent, dividing infrequently to produce heterogeneous populations of rapidly dividing neural precursor cells (NPCs). Under normal physiological conditions, NPCs in the SVZ and SGZ differentiate into cells destined to become interneurons in the olfactory bulb and granule neurons in the dentate gyrus, respectively (Lois and Alvarez-Buylla, 1994; Seri et al., 2001). In vitro characterisation of cells isolated from the SVZ and dentate gyrus provided additional experimental evidence to define both regions as persistent neurogenic niches in the adult rodent CNS (Reynolds and Weiss, 1992; Richards et al., 1992; Walker et al., 2008). When cultured at low density in the presence of epidermal growth factor (EGF) and/or fibroblast growth factor-2 (FGF-2), neural stem/progenitor cells isolated from the SVZ and dentate gyrus generate clonally derived spheres of cells known as neurospheres. A subset of neurospheres exhibit the cardinal properties of stem cells including the ability to proliferate, self-renew and undergo multipotential differentiation, generating neurones, astrocytes and oligodendrocytes (reviewed by Pastrana et al., 2011). Long-term examination of single cells within the adult neurogenic niches also support the existence of multipotent neural stem/progenitor cells in vivo (Bonaguidi et al., 2011).

Please cite this article in press as: Merson TD, Bourne JA. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.003

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Although we now know a great deal about the cellular and molecular processes that orchestrate adult neurogenesis in rodents (reviewed by Faigle and Song, 2013), efforts to extend our understanding of adult neurogenesis to the human brain are still in their infancy. In vitro analyses have demonstrated that cells in the SVZ and hippocampus of the adult human brain contain multipotent neurospheres (Eriksson et al., 1998; Kukekov et al., 1999; Roy et al., 2000). Histological analyses of post-mortem human brain specimens have defined the SVZ (Sanai et al., 2004, 2011; Wang et al., 2011) and an RMS-like structure (Curtis et al., 2007; Wang et al., 2011), although the existence of the latter has been disputed (Sanai et al., 2004, 2007, 2011). The extent to which neurogenesis in the adult human SVZ generates new neurons remains unresolved. On the one hand, Curtis et al. (2007) provided histological evidence that dividing neuroblasts exist within a putative human RMS and that newborn neurons are found in the adult human olfactory bulb. On the other hand, birth-dating of olfactory bulb neurons by quantifying nuclear bomb test-derived 14 C concentrations suggests that there is very limited, if any, postnatal neurogenesis in this structure (Bergmann et al., 2012), consistent with the absence of neuroblasts in the adult human olfactory bulb described by Wang et al. (2011). Using the same radiocarbon dating approach, the Frisén laboratory has recently published evidence for substantial lifelong turnover of striatal interneurons in the adult human brain and immunohistochemical data confirming the presence of neuroblasts and newborn neurons in the adult human striatum (Ernst et al., 2014). Although independent verification will be required, the data strongly argue that neural stem/progenitor cells in the adult human SVZ generate interneurons that specifically migrate into the striatum instead of the olfactory bulb. In addition, radiocarbon dating of hippocampal neurons has also provided clear evidence for significant neuronal turnover in the normal adult human hippocampus (Spalding et al., 2013). It is now clear that certain types of brain injury, including ischaemic stroke, induce cellular and molecular changes that activate the adult neurogenic niches resulting in modulation of NPC proliferation, differentiation, migration and/or survival In rodent model, ischaemic stroke has been demonstrated to promote the ectopic migration of SVZ-derived NPCs into the post-ischaemic striatum (Parent et al., 2002; Yamashita et al., 2006; Hou et al., 2008; Zhang et al., 2009), CA1 region of the hippocampus (Nakatomi et al., 2002; Bendel et al., 2005) or cerebral cortex (Jin et al., 2003; Leker et al., 2007; Kreuzberg et al., 2010; Ohira et al., 2010), where they differentiate into neurons or glia. Histological examination of brain tissue from stroke-affected individuals has revealed increased proliferation of NPCs in the SVZ (Arvidsson et al., 2002; Macas et al., 2006; Martí-Fàbregas et al., 2010) and the presence of cells in the ischaemic penumbra of the cerebral cortex or striatum that expressed markers of NPCs or immature neurons (Arvidsson et al., 2002; Jin et al., 2006; Nakayama et al., 2010). However, post-mortem neuronal birthdating by nuclear 14 C measurement of cortical neurons from stroke-affected individuals failed to provide any evidence for the generation of new cortical neurons between 3 days and 13 years after stroke (Huttner et al., 2014). On the basis of additional histological analyses, Huttner et al. (2014) suggested that the maximum amount of undetected ischaemia-induced neurogenesis in their analyses would be less than 0.1% (1 in 1000 neurons). Thus is seems likely that the generation of new cortical neurons following stroke in the human is at best minimal but this does not formally exclude the possibility of low-level neuron production, as has been identified following stroke in rodents, nor is it inconsistent with a post-ischaemic proliferative response of the human SVZ that has been identified by numerous previous studies. In addition, given the recent demonstration of substantial interneuron turnover in the adult human striatum (Ernst et al., 2014), further studies to directly examine whether ischaemic

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Although adult neurogenesis does not normally occur under basal conditions in the striatum of healthy rodents, genetic fate-mapping studies tracing the migration of NPCs in the post-ischaemic brain have provided definitive evidence that SVZderived NPCs migrate ectopically into the ischaemic penumbra of non-neurogenic regions of the adult brain including the striatum and cerebral cortex. For example, Kreuzberg et al. (2010) recently used 5HT3A-EGFP transgenic mice in which all neuroblasts originating in the SVZ express EGFP under the control of the promoter for serotonin receptor 5HT3A and downregulate EGFP in all neurons except for those that continue to express 5HT3A receptors at maturity. BrdU-incorporation after stroke revealed an increase in EGFP+/BrdU+ neuroblasts in the ipsilateral hemisphere 14 and 35 days post stroke. They noted that some EGFP+ cells migrated to the neocortex and survived for at least 35 days and differentiated into neurons. An alternate approach for genetic fate mapping relies upon use of transgenic mice expressing a fusion protein of Cre recombinase and mutated oestrogen receptor placed under the regulatory control of a promoter that is specifically active in the cell type of interest to enable tamoxifen-dependent expression of a reporter gene (Metzger and Chambon, 2001). Zhang et al. (2011) traced the fate of cells expressing the basic helix–loop–helix transcription factor Ascl1 (also known as Mash1), a marker of transit amplifying cells in the SVZ. Ascl1-CreER(TM):R26R-stop-yellow fluorescent protein (YFP) transgenic mice were subject to permanent right MCAO then injected with tamoxifen after 48 h to induce permanent YFP expression in Ascl1-expressing cells. They observed an increased number of fate-mapped cells 7 days after stroke, specifically in the ipsilateral SVZ, striatum and corpus callosum which subsequently gave rise to GABAergic interneurons and mature oligodendrocytes. Similarly, fate-mapping of nestin-expressing SVZ cells, using nestin-CreER(T2):R26R-stop-YFP mice, revealed migration of nestin-expressing cells into the ischaemic striatum where they differentiated into both neurons and oligodendrocytes as well as NPC migration into the corpus callosum whereupon they generated oligodendrocytes, effects that were potentiated by treatment with the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil (Zhang et al., 2012). Interestingly, Zhang et al. (2011) identified that the pool of proliferative Ascl1 fate-mapped NPCs peaked in the striatum 14–30 days after ischaemia whereas proliferation in the SVZ peaked at 7 days. This suggests that SVZ-derived progenitors continue to proliferate within the striatum before subsequently differentiating into neurons and oligodendrocytes. This lends support to an emerging idea that this domain within the striatum could represent an ectopic germinal niche that is generated in response to the ischaemic injury. Recent evidence in the rat MCAO model supports to this idea. It has been demonstrated that whereas ependymal cells lining the lateral ventricles were predominantly non-proliferative and their numbers in the SVZ reduced at 6 and 16 weeks post stroke, non-proliferative ependyma-like cells were present in the striatum in association with blood vessels (Danilov et al., 2012). It will be fascinating to establish whether these cells migrate from the SVZ and whether they assist in guiding neuroblasts to ischaemic boundary along blood vessels. Ischaemia also potentiates neurogenesis in the subgranular zone of the hippocampal dentate gyrus however neurons generated in this germinal niche do not appear to migrate ectopically

Please cite this article in press as: Merson TD, Bourne JA. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.003

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from their normal destination within the granule cell layer. Using a mouse model of photothrombotic infarction targeting the sensorimotor cortex, Keiner et al. (2010) were able to demonstrate that neurogenesis is potentiated not by increasing proliferation of neural stem cells (radial glia-like type 1 cells) but by a selective expansion in the population rapidly proliferating type-2 cells (transit-amplifying cells) and immature neurons and by potentiating the survival of mature neurons.

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Accumulating evidence suggests that the recruitment of SVZderived NPCs may not be the only mechanism responsible for the generation of neurons in the peri-infarct areas of the neocortex. Additional lines of evidence suggest that local progenitors residing in the neocortex could proliferate and differentiate into new neurons in response to cortical injury in rodents (Magavi and Macklis, 2002; Buffo et al., 2008) and nonhuman primates (Vessal et al., 2007; Rosenzweig et al., 2010; Vessal and Darian-Smith, 2010). An important lead to understanding neocortical neurogenesis following injury is the finding that non-neurogenic compartments of the uninjured rodent, nonhuman primate and human CNS contain multipotent NPCs that exhibit latent neurogenic potential in vitro (Palmer et al., 1999; Laywell et al., 2000; Nunes et al., 2003; Matsumura et al., 2003; Jiao and Chen, 2008; Buffo et al., 2008; Shimada et al., 2010, 2012; Homman-Ludiye et al., 2012; Ahmed et al., 2012; Lojewski et al., 2014). The precise identity of the cell type(s) responsible for this latent in vitro neurogenic potential remains poorly defined. Two potential candidates are NG2-glia and parenchymal astrocytes (reviewed by Dimou and Götz, 2014). NG2-glia are defined by the expression of NG2 proteoglycan and PDGFR␣ and also express Sox10, Olig1 and Olig2. Genetic fate-mapping of NG2-glia using various transgenic strategies utilising either NG2creERTM BAC (Zhu et al., 2011a,b), PDGFR␣-CreERT2 (Kang et al., 2010; Rivers et al., 2008) or Olig2::CreERTM (Dimou et al., 2008) transgenic lines, have consistently demonstrated that NG2-glia generate mature oligodendrocytes under basal conditions in the adult mouse brain (Richardson et al., 2011). Early reports that NG2-glia can also generate small numbers of projection neurons in the piriform cortex or parenchymal astrocytes under basal conditions have not been reproduced, and the prevailing view is that NG2-glia self-renew to generate new NG2-glia or oligodendrocytes in the healthy brain (Richardson et al., 2011; Dimou and Götz, 2014). Under injury conditions, NG2-glia proliferate extensively and a small proportion of these cells acquire the potential to differentiate into astrocytes (Tatsumi et al., 2008; Tripathi et al., 2010). It has also been demonstrated that certain extracellular signals can convert early postnatal NG2-glia into multipotent neural stem cells in vitro (Kondo and Raff, 2000, 2004). It remains to be determined whether endogenous reprogramming of NG2 glia in the adult CNS could occur in response to ischaemic or other types of brain injury. Parenchymal astrocytes are another class of glial cell that has been examined for latent neurogenic potential in the context of injury. Although non-mitotic under basal conditions, parenchymal astrocytes proximal to a cortical stab wound injury or cerebral ischaemia rapidly proliferate and acquire neural stem cell-like properties that are evident following in vitro cell culture (Shimada et al., 2012; Sirko et al., 2013). Genetically fate mapped parenchymal astrocytes isolated from the ischaemic penumbra of mice acquired the capacity to generate multipotent neurospheres (Buffo et al., 2008; Sirko et al., 2013). However, these cells did not appear to be capable of generating neurons following transplantation, even after grafting into the SVZ (Shimada et al., 2012), suggesting that their neurogenic potential in vivo is inhibited by as yet to be defined signals.

Direct evidence to support the notion that ischaemia activates a latent neurogenic capacity in NPCs residing in the neocortex independent of responses occurring in the SVZ or SGZ has emerged from two recent studies. Comparison of the temporal profile of cell proliferation in adult rat SVZ and dentate gyrus after transient MCAO, with the time-course of acquisition of new neurons in the peri-infarct area of the cerebral cortex, raised the possibility that neurogenesis could be initiated locally within the neocortex (Kuge et al., 2009). It was subsequently demonstrated using retroviral labelling approaches that NPCs residing in layer 1 of the rat neocortex proliferated in response to global forebrain ischaemia and generated GABAergic neurons that functionally integrated into the circuitry (Ohira et al., 2010). An issue of particular relevance to research translation will be to establish whether neurogenesis can occur locally within the neocortex of animals with larger brains than rodents in which the issue of migratory distances between germinal zones and the neocortex are much greater. Data to address this question are limited but it has been suggested that post-ischaemic neurogenesis in the neocortex of the nonhuman primate cannot be explained by recruitment of SVZ-derived NPCs (Tonchev et al., 2005). Similarly, the identification of putative neural stem/progenitor cells in the post-ischaemic human cerebral cortex has raised the perspective that these cells could potentially arise from normally quiescent cells localised close to the injury site (Arvidsson et al., 2002; Nakayama et al., 2010). Given recent findings challenging the notion that neurogenesis can occur in the post-ischaemic human neocortex (Huttner et al., 2014), all available data must be submitted to careful interpretation and new studies must be devised to corroborate previous results. Thus although neocortical neurogenesis has been readily documented in the post-ischaemic rodent, and local progenitors appear to be recruited, additional studies in nonhuman primates would help establish the extent that this occurs in larger primate brains. If this can be further corroborated, establishing the relative contribution of neurogenesis in adult germinal zones versus that proximal to the ischaemic injury will be important, as will be determining the molecular mechanisms that regulate and modulate each of these processes. 5. Vascular remodelling & neurogenesis The intimate relationship between the processes of postischaemic angiogenesis, vascular remodelling and neurogenesis are becoming increasingly clear. This is perhaps not surprising given the seminal studies demonstrating the close link between angiogenesis and neurogenesis during brain development. It is known that endothelial cells in the adult SVZ create a vascular niche that supports neurogenesis and neuronal differentiation under normal physiological conditions (Leventhal et al., 1999; Shen et al., 2008; Tavazoie et al., 2008) and accumulating data suggest that angiogenic and neurogenic responses to ischaemia are also closely linked (Vissapragada et al., 2014). Angiogenesis results in the generation of new blood vessels that increase collateral circulation around the lesion core (Zhang et al., 2002; Beck and Plate, 2009). An emerging view is that interactions with endothelial cells facilitate neurogenesis by providing directional cues for neuroblast migration and/or by acting as a scaffold for neurogenesis (reviewed by Font et al., 2010). After ischaemia, NPCs have been found to associate with both the pre-existing and newly generated blood vessels in the ischaemic striatum (Kojima et al., 2010). Increasing vascular remodelling in the ischaemic brain by viral-mediated expression of human angiopoietin-1 (Ang-1) was found to accelerate neuronal differentiation of NPCs (Meng et al., 2014). Co-administration of human-derived endothelial progenitor cells and smooth muscle progenitor cells both increased maturation of vascular phenotype and maintained neurogenesis and neuroblast migration to

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the infarcted neocortex (Nih et al., 2012). It has also been demonstrated that stroke upregulates expression of the pro-angiogenic gene angiopoietin 2 (ANG2) in the SVZ. In vitro ANG2 promoted NPC migration via a matrix metalloproteinase (MMP)-dependent mechanism and upregulated neuronal differentiation of NPCs by upregulating C/EBP-␤, a transcription factor that activates the promoter of the ␤III tubulin gene (Liu et al., 2009). Recent studies have highlighted how other vascular products that deposit within the ischaemic milieu could influence neurogenesis. In particular, new data have emerged on the role that platelets might play in mediating this process. Platelets tend to accumulate when permeability of the BBB increases after stroke, where they provide a scaffold for activation the coagulation cascade. Experimental delivery of platelet lysate into the lateral ventricles was found to increase angiogenesis and neurogenesis, reduce the size of the ischaemic lesion and improve neurological outcome after cerebral ischaemic (Hayon et al., 2013). Similarly, delivery of growth factor rich platelet-derived microparticles onto the surface of the brain of rats subject to permanent MCAO increased cell proliferation, neurogenesis and angiogenesis at infarct boundary zone (Hayon et al., 2012). Delineating which components of platelets are responsible for these effects will be important for establishing the signalling components that drive these beneficial responses. 6. Relevance of ischaemia-induced neurogenesis to functional recovery Cognitive deficits, including memory impairment, are a frequent co-morbidity of ischaemic stroke. Improvement in cognitive deficits can be explained, at least in part, by neuroplastic changes that reorganise connections between surviving neurons (reviewed by Pekna et al., 2012). However, increasing evidence supports the possibility that hippocampal neurogenesis, a process that facilitates spatial and object memory in normal healthy brain (reviewed by Glasper et al., 2012), could also be an important for cognitive improvement after stroke. One approach to test this idea has been to examine the consequences of either potentiating or blocking neurogenesis in the context of ischaemic stroke. Enhancing neurogenesis has generally been demonstrated to improve behavioural outcomes following ischaemic stroke, whereas disrupting neurogenesis has the reverse effect. For example, administration of the antidepressant fluoxetine to mice after MCAO potentiated the survival of newborn neurons and attenuated spatial memory impairment (Li et al., 2009b). Conversely, blocking hippocampal neurogenesis using 3-azido-deoxythymidine (AZT) inhibited the beneficial effects of fluoxetine treatment upon spatial cognitive function. Similar results have been obtained by conditional deletion of neuroblasts that provide more compelling evidence of a link between neurogenesis and cognitive recovery. Using transgenic mice that express the herpes simplex virus thymidine kinase (HSV-TK) under the control of the doublecortin (DCX) promoter enabled conditional ablation of neuroblasts in the SVZ and dentate gyrus following gancyclovir (GSV) treatment, a pro-drug which is metabolised to a toxic metabolite in HSV-TKexpressing neuroblasts (Jin et al., 2010a). GCV treatment of DCX-TK mice also increased infarct size and exacerbated post ischaemic sensorimotor behavioural deficits in both young and middle-aged mice that were evident just 1 day after cell ablation, suggesting that neurogenesis contributes to acute stroke outcome (Jin et al., 2010a; Sun et al., 2012). The adverse effects of transiently ablating neural stem cells were also persistent since the volume of tissue loss remained greater in DCX-TK(+) than in control young-adult mice for at least 12 weeks after an MCAO, whereas neurobehavioral deficits were only worse in DCX-TK(+) mice for up to 8 weeks before reaching equivalence by 12 weeks after MCAO, when incidentally, neurogenesis in SVZ and SGZ also returned to normal levels. Thus it

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appears that transiently disrupting neurogenesis results in an early persistent effect on lesion volume, whereas its effect on clinical course is transient (Wang et al., 2012a). Collectively, these findings add further support to the notion that endogenous neurogenesis exerts a beneficial influence on stroke outcome. However the observation that blocking ischaemia-induced neurogenesis exerts an acute detrimental upon ischaemic lesion size suggests that neurogenesis does not exert all its effects via the production of new neurons that integrate into the neural circuitry. Even though neuroblasts migrate to sites of ischaemic injury for many months after infarction (Thored et al., 2006; Leker et al., 2007), relatively few of these cells survive as mature differentiated neurons. The results suggest that NPCs could also possess an important trophic function that could protect vulnerable neural tissue from acute loss following ischaemia and could provide long-term trophic support to limit neurodegeneration. 7. Trophic function of NPCs in promoting cell survival and/or synaptic plasticity The emerging concept that adult neurogenesis could provide beneficial trophic effects that limits neurodegeneration at acute and subacute stages after ischaemic stroke is supported by the observation that only a small portion of SVZ-derived cells differentiate into functional mature neurons (Arvidsson et al., 2002). Most newborn cells in the SVZ appear to die during migration after focal ischaemia. Acute loss of NPCs before they have differentiated into mature neurons also results in immediate tissue loss, suggesting that a major component of the beneficial effect of potentiated neurogenesis could be in the provision of trophic support via delivery of neurotrophins and growth factors that support cell survival and/or neuroplasticity (reviewed by Kernie and Parent, 2010). Additional data have recently emerged that support this concept. Potentiating Wnt signalling by injecting a Wnt3a-expressing lentivirus into the striatum was demonstrated to increase neurogenesis within the ischaemic striatum and improve neurological outcome by 28 days after endothelin-1-induced focal ischaemia (Shruster et al., 2012). However, when the virus was injected directly into the SVZ, the outcome was improved just 2 days after ischaemia and was associated with an increased density of immature neurons in both the striatum and SVZ (Shruster et al., 2012). The study is consistent with the view that acute neuroprotection occurs principally by potentiating SVZ neurogenesis and enhancing the rapid recruitment of immature neurons to the ischaemic striatum, rather than providing acute neuroprotection locally within the post-ischaemic striatum. Experimental interventions that block NPC recruitment also increase infarct size, providing a conceptual link between potentiated neurogenesis and neuroprotection. Intraventricular infusion of the anti-mitotic cytosine ␤-d-arabinofuranoside (AraC) during the first 7 days after brain ischaemia completely abolished NPC proliferation in SVZ and dramatically reduced NPC proliferation in the dentate gyrus. This reduced neuronal density in CA1 and CA3, enlarged infarct size and worsened neurological deficits caused by ischaemia (Li et al., 2010a). Importantly, NPC-conditioned media demonstrated neuroprotective effects in an in vitro assay of glutamate-mediated excitotoxicity of cortical neurons. Brainderived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) within conditioned medium was shown to be required for these beneficial effects, suggesting that NPCderived trophic factors are a component of the protective role of neural stem/progenitor cells in post-ischaemic responses (Li et al., 2010a). It has also been demonstrated that SVZ-derived NPCs recruited into the post-ischaemic striatum could protect striatal neurons from glutamatergic excitotoxicity via secretion of endocannabinoids (Butti et al., 2012). The release of the

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endocannabinod arachidonoyl ethanolamide from SVZ-derived NPCs was demonstrated to reduce glutamatergic tone on medium spiny striatal neurons via binding to type 1 cannabinoid receptors (CB1). Moreover, the increased morbidity and mortality caused by conditional ablation of SVZ NPCs in mice subjected to MCAO could be reversed by pharmacologically restoring cannabinoid levels in the post-ischaemic striatum (Butti et al., 2012), suggesting that endocannabinod production by SVZ-derived NPCs is an important component of their neuroprotective activity after stroke. Other data support the possibility that aberrant neurogenesis in the dentate gyrus could contribute to comorbidities including cognitive impairment or epilepsy. Abnormal integration of newborn neurons into hippocampal circuits could result in abnormal modulation of mood-related behaviours, and the development of post-stroke epilepsy. Niv et al. (2012) recently demonstrated that new dentate gyrus granule cells generated in response to ischaemia were located ectopically in the dentate gyrus and they exhibited morphological abnormalities. Despite their abnormal localisation and morphology, these newborn neurons had a high density of mushroom spines on their dendrites suggesting that they integrated into the local circuitry. These positional and morphological anomalies were more severe in more substantially infarcted animals signifying that aberrant integration may contribute to functional impairments in the post-ischaemic brain.

8. Hormonal regulation of neurogenesis Recent data have highlighted the role of sex hormones in potentiating ischaemia-induced neurogenesis. Extensive studies in animal models of ischaemic stroke have demonstrated that acute administration of estrogens exerts potent neuroprotective activity against ischaemia-induced brain damage, although these findings have thus far failed to translate into clinical benefit (reviewed by Liu and Yang, 2013). In addition to neuroprotective effects observed in many animal studies, estrogens have more recently been demonstrated to potentiate post-ischaemic neurogenesis (reviewed by Suzuki et al., 2009). The principal mammalian oestrogen, 17-beta-estradiol (E2 ), has previously been demonstrated to enhance the production of adult-born neurons in the ischaemic brain (Suzuki et al., 2007). Provision of physiological levels of estradiol prior to stroke, selectively increased the number of neuroblasts detected in the SVZ of mice 96 h after ischaemic stroke but did not alter neurogenesis in uninjured sham controls. Both oestrogen receptor alpha (ER␣) and beta (ER␤) were found to be required since enhancement of neurogenesis following E2 administration in ischaemic mice was abolished in both ER␣ knockout and ER␤ knockout mice (Suzuki et al., 2007). The clinically relevant selective oestrogen receptor modulator raloxifene but not tamoxifen was also found to increase post-ischaemic neurogenesis to a similar extent as E2 (Khan et al., 2014). The longterm survival of new neurons generated in response to pre-stroke E2 stimulation was subsequently confirmed in the dentate gyrus at 6 weeks after ischaemic stroke (Li et al., 2011). Genetic deletion of either ER␣, ER␤ or P450 aromatase, the enzyme that synthesises E2 from C19 steroids (Hojo et al., 2004), abolished the stroke-induced increase in SVZ and hippocampal neurogenesis (Li et al., 2011). More recently, it was demonstrated that post-stroke delivery of E2 also potentiated neurogenesis in the ipsilateral SVZ in an adult rat MCAO model (Zheng et al., 2013). In contrast to estrogens, little is known about the effect of androgens on stroke-induced neurogenesis. It has recently been demonstrated that castration or androgenR blockade in male mice did not affect post-ischaemic neurogenesis but long-term androgenR blockade reduced maturation of dentate gyrus neurons (Zhang et al., 2014). Higher than normal levels of testosterone

blocked post-ischaemic neurogenesis in dentate gyrus and dihydrotestosterone almost abolished neurogenesis (Zhang et al., 2014).

9. Inflammatory regulation Neuroinflammation is an important component of the pathogenic response to ischaemic stroke. At the subacute stages inflammatory responses are believed to create a microenvironment that is deleterious to the survival of newborn neurons (Zhou et al., 2011). However the counter view is that some chemokines involved in the inflammatory response could facilitate neuroblast migration to the ischaemic site. As a consequence, immunomodulatory interventions could have differential effects upon neurogenesis by influencing specific aspects of post-ischaemic neurogenesis that affects cell survival, migration and/or differentiation. One approach to investigate the broad effects has been to block the activation of innate immune cells after ischaemic stroke. The tetracycline antibiotic minocycline suppresses microglial cell activation under various circumstances and it was thus reasoned that use of minocycline as a treatment for ischaemic stroke could potentially reduce infarct size by preventing secondary damage caused by stroke-induced neuroinflammation. Contrary to this a priori view, recent data examining the effect of minocycline in models of ischaemic stroke produced inconsistent data. On the one hand, minocycline treatment has been demonstrated to attenuate microglial cell activation in the post-ischaemic CNS but did not have any neuroprotective or behavioural benefit and reduced stroke-induced neurogenesis (Kim et al., 2009a, 2010). On the other hand, another study found that minocycline did not reduce strokeinduced neuroinflammation and increased neural stem cell activity in the SVZ and dentate gyrus (Rueger et al., 2012). In fact application of minocycline to foetal rat NPC cultures was found to enhance cell survival without modulating proliferation (Rueger et al., 2012). Thus the precise role of innate immune cell activity in regulating neurogenesis following ischaemic stoke requires further investigation. Another important component of the neuroinflammatory cascade involves activation of the classical, alternative, and lectin complement pathways. It has been demonstrated that the production of anaphylatoxins C3a and C5a potentiates leucocyte recruitment, cytokine release and the production of reactive oxygen species (reviewed by Banz and Rieben, 2012). Inhibiting complement C3a in the post-ischaemic brain is thought to be a rational approach to inhibit the inflammatory cascade. It has now emerged that inhibiting the effects of C3a by receptor blockade in a transient focal cerebral ischaemia model in mice enhanced SVZ neuroblast proliferation, reduced T-cell density and improved neurological outcome (Ducruet et al., 2012). A recent focus of investigation has been to understand the role of matrix metalloproteinases (MMPs) in ischaemic stroke and neurogenesis. MMPs are secreted or membrane-bound zincdependent endopeptidases that degrade bioactive proteins and membrane receptors resulting in degradation and turnover of the extracellular matrix (reviewed by Jin et al., 2010b). The secretion of MMPs from endothelial cells and neutrophils following ischaemic stroke degrades neurovascular matrix resulting in disruption of blood–brain-barrier (BBB) tight junctions and leads to brain oedema and haemorrhage (Sandoval and Witt, 2008). Inhibition of MMP activity has therefore come to the fore as a potential drug intervention to prevent BBB leakage in acute stroke. However, recent studies have demonstrated that ischaemic stroke induces elevated expression of MMP-2 and MMP-9 by newborn neurons in the dentate gyrus in nonhuman primates (Lu et al., 2008). In particular, MMP-9 has been proposed to facilitate neuroblast migration after ischaemic stroke (Lee et al., 2006; Barkho et al.,

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Vascular endothelial growth factor (VEGF) acts as both angiogenic and vascular permeability factor and has also been identified to exert neurotrophic activities. VEGF has been reported to potentiate NPC proliferation (Zhu et al., 2003) and acts as a chemoattractant during NPC migration (Zhang et al., 2003). Molecular analyses of SVZ tissue following ischaemia have demonstrated that both VEGF-A and VEGF receptor-1 are upregulated following stoke (Sun et al., 2010). AAV-mediated overexpression of VEGF in rats subjected to transient MCAO reduced infarct size, reduced neurological deficits and potentiated NPC proliferation in the SVZ and promoted migration to the ischaemic lesion (Li et al., 2009a). Although NPCs in the SGZ also proliferated in response to VEGF overexpression these newborn neurons remained confined to the dentate gyrus (Li et al., 2009a). Collectively the data reveal that VEGF acts as a mitogen and chemoattractant for migrating NPCs and offers a mechanistic link between angiogenic and neurogenic responses to ischaemic stroke.

underlie this beneficial effect. In particular, the potential for proneurogenic effects is supported by the finding that EPO and the EPO receptor (EPOR) are expressed in the germinal zones of the developing and adult CNS where they act in an autocrine–paracine manner to regulate the production of neuronal progenitors (Shingo et al., 2001). Ischaemic stroke upregulates the expression of EPO and EPOR in the CNS (Li et al., 2010b), and administration of exogenous EPO potentiates SVZ neurogenesis (Wang et al., 2004) whereas CNSspecific knockdown of EPOR impairs post-ischaemic neurogenesis (Tsai et al., 2006). Recent studies indicate that exogenous EPO also exerts proneurogenic activity in the neonatal ischaemic brain. In a neonatal rat model of MCAO, treatment with exogenous EPO potentiated NPC proliferation in the SVZ resulting in increased generation of SVZ-derived neurons and oligodendroglia that migrated to sites of ischaemic injury (Gonzalez et al., 2013). Interestingly, a concomitant reduction in the generation of SVZ-derived astrocytes was identified suggesting that EPO treatment selectively promoted neurogenesis and oligodendrogenesis at the expense of astrogliogenesis (Gonzalez et al., 2013). The capacity of EPO to favour neuronal fate commitment and potentiate NPC proliferation has been corroborated in an ex vivo organotypic slice culture model of oxygen-glucose deprivation (Osredkar et al., 2010). Concerns have been raised that the treatment of stroke patients with EPO could increase the risk of thrombotic events because the erythropoietic effects of EPO could increase blood viscosity (Lapchak, 2010). Importantly, it has been demonstrated that non-erythropoietic EPO analogues such as carbamylated EPO (CEPO), which selectively bind the non-erythropoietic EPOR/CD131 heterodimer but do not bind the erythropoietic homodimer, are neuroprotective (Minnerup et al., 2009) and still exert pro-neurogenic activity (Wang et al., 2007). The finding that EPO treatment following ischaemia selectively potentiates SVZ production of neuroblasts at the expense of astrocytes could however have detrimental consequences. It has recently been demonstrated that large numbers of astrocytes generated from SVZ progenitors after photothrombotic/ischaemic cortical injury migrate to the lesion border to create a glial scar (Benner et al., 2013). SVZ-derived astrocytes appear to differ from reactive parenchymal astrocytes as the former express high levels of the secreted glycoprotein thrombospondin 4 (Thsp4). It also turns out that Thsp4-expressing SVZ progenitors participate in injury-induced transduction of heightened Notch signalling, and Thsp4 knockout mice have impaired infarct-induced SVZ astrogliogenesis, favouring the generation of Dcx-positive neuroblasts. The impaired recruitment of SVZ-derived astrocytes to the ischaemic lesion in Thsp4 knockout mice was associated with a poorly formed/disorganised glial scar as well as significant haemorrhage and oedema around the ischaemic region (Benner et al., 2013). This finding adds to the growing perspective that astrocytes exert both beneficial and detrimental roles in injury responses (reviewed by Sofroniew, 2014). It now appears that astrocytes produced in the SVZ following cortical ischaemia could have particular beneficial qualities that are not afforded equally by reactive astrocytes within the parenchyma. The notion that therapeutic interventions targeting the SVZ should favour neuronal production at the expense of astrogliogenesis is therefore too simplistic a view.

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10.3. EPO

10.4. LNK adapter protein

Erythropoietin (EPO) has long been identified as a critical cytokine for red blood cell production during haematopoiesis (Longmore et al., 1993) and also elicits potent angiogenic activity (Ribatti et al., 1999). In ischaemic stroke, exogenous EPO is neuroprotective, reducing infarct size and improving neurobehavioral deficits (Minnerup et al., 2009). Multiple modes of action likely

The intrinsic adaptor protein LNK, previously known for its key role in inhibiting the proliferation of hematopoietic stem cells (Buza-Vidas et al., 2006) and endothelial cells (Kwon et al., 2009), has now been identified as a stroke-specific negative regulator of NPC proliferation. Ahlenius et al. (2012) have demonstrated that LNK is expressed by NPCs in the normal adult SVZ, and that LNK

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2008; Kang et al., 2008). These results have been corroborated by recent studies demonstrating a close correlation between the spatiotemporal expression of MMPs in the dentate gyrus after cerebral ischaemia and the increased rate of proliferation and differentiation of progenitor cells into mature neurons (Wojcik et al., 2009; Wojcik-Stanaszek et al., 2011). Collectively, the data cement the view that MMPs exert both beneficial and deleterious effects after ischaemia, both provoking BBB leakage leading to neuronal cell death on the one hand yet also facilitating neovascularisation and neurogenesis on the other.

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10. Cell signalling molecules In this section of the review, we highlight recent research that has implicated various signalling molecules in the regulation of post-ischaemic neurogenesis (summarised in Table 1). We reflect on recent studies examining the potential of both previously known molecular mediators and draw attention to new players that will inform future directions for research into mechanisms of action over the next 5–10 years. 10.1. TGF-alpha The transforming growth factor alpha (TGF-␣) is a potent mitogen and neurotrophic factor that has been demonstrated to exert diverse beneficial activities in the post-ischaemic brain. With regards to post-ischaemic neurogenesis, TGF-␣ infusion into the ischaemic brain was found to significantly increase nestin expression within the neurogenic niches (Alipanahzadeh et al., 2013), potentiate NPC proliferation and enhance the migration and subsequent differentiation of neuroblasts into the ischaemic region, although it was administered 4 weeks after MCAO (Guerra-Crespo et al., 2009). Improved behavioural outcomes observed in TGF-␣ injected animals likely reflects additional neuroprotective activities which could include potentiation of neovascularisation (Leker et al., 2009). 10.2. VEGF

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Table 1 Recent in vivo molecular manipulations utilised in the context of cerebral ischaemia or in vitro oxygen/glucose deprivation and their resultant effects upon neurogenesis. tMCAO/pMCAO, permanent/transient middle cerebral artery occlusion; tBCCAO, transient bilateral common carotid artery occlusion; Et-1, endothelin-1; OLs, oligodendrocytes; prolif., proliferation. Factor

Experimental manipulation

Stroke model

Effect on post-ischaemic neurogenesis

References

Angiopoietin-1 BDNF

Lentiviral overexpression Anti-BDNF IgG (10 ng/h, ICV) for 14d starting 4d before hypoxia SB290157 (C3a-receptor antagonist, 1 mg/kg) Cerebrolysin (1–5 mg/kg, i.p.) for 21d starting 1d after stroke CNTF−/− mice Surface delivery of EGF in hydrogel 4d after stroke Ephrin-B3−/− mice EPO (1000 U/kg, i.p.) at reperfusion then at 1d & 7d Single gene knockout mice

Rat tMCAO Rat intermittent hypoxia for 14d

↑ Neurogenesis ↓ Post-ischaemic NPC prolif. in DG

Meng et al. (2014) Zhu et al. (2010)

Mouse tMCAO

↑ neuroblast prolif. in SVZ

Ducruet et al. (2012)

Rat pMCAO

↑ NPC prolif. & density of neuroblasts in ipsilateral striatum ↓ Post-ischaemic NPC prolif. in SVZ ↑ Post-ischaemic neurogenesis

Zhang et al. (2010)

Doeppner et al. (2011) Gonzalez et al. (2013)

Mouse tMCAO

↑ NPC prolif. ↑ NPC prolif. in SVZ, ↑ SVZ-born neurons & OLs Blocked stroke-induced neurogenesis in SVZ & DG ↑ Generation of granule cells in DG

Rat tMCAO

↑ Post-ischaemic neurogenesis

Khan et al. (2014)

Neonatal (P3) rat BCCAO

↑ Post-ischaemic NPC prolif. in SVZ

Jin-Qiao et al. (2009)

Mouse tMCAO

Suppressed maturation of newborn neurons in DG

Zhang et al. (2014)

Mouse tBCCAO

↑ BDNF expression in GFAP+ cells in DG, ↑ density of DCX+ cells in both SVZ & DG ↑ NPC prolif. in SVZ of Lnk−/− mice after MCAO ↑ NPC prolif. in SVZ, ↑ neuroblast migration & neuronal maturation

Okuyama et al. (2012)

↓ Post-ischaemic neurogenesis in SVZ Negligible effect on post-ischaemic neurogenesis in SVZ ↑ Number of Sox2+ NPCs in SVZ

Kim et al. (2009a)

↑ Newborn neuron survival in striatum & SVZ; normal prolif. ↑ Generation of neuroblasts in SVZ

Zhu et al. (2011a,b)

Blocked ischaemia-induced neurogenesis & ↑ neuronal differentiation of residual NPCs ↑ Neurogenesis

Wang et al. (2009a)

Rat pMCAO Mouse tMCAO

↑ NPC prolif. & neuron production Blocked ischaemia-induced NPC prolif. in SGZ

Hayon et al. (2012) Sims et al. (2009)

Rat pMCAO

↑ NPC prolif. & ↑ neuron production in SVZ & DG Inhibited production of neuroblasts in DG

Kim et al. (2009b)

Rat tMCAO

↑ NPC prolif., migration & neuronal differentiation

Guerra-Crespo et al. (2009)

Mouse tBCCAO

↑ NPC prolif. & generation of new neurons in DG ↑ Generation of neurons & OLs in ischaemic boundary ↑ NPC prolif. in SVZ & DG ↑ NPC migration (SVZ → lesion) ↑ Generation of neurons in ipsilateral striatum

Tian et al. (2014)

C3a-receptor Cerebrolysin CNTF EGF Ephrin-B3 EPO ER␣, ER␤, & aromatase 17␤-estradiol (E2 ) or raloxifene

FGF-2

Flutamide (androgenR inhibitor)

Heptamethoxyflavone (HMF)

LNK adapter protein Meteorin

Minocycline

miR17-92 cluster NGF Notch1

Platelet lysate Platelet microparticles Smoothened (Smo)

Sodium butyrate (SB) Testosterone & DHT

TGF-␣

Thioredoxin-1 Valproic acid (VPA) VEGF Wnt3a

E2 infusion starting 1wk before stroke Infusion of 25 ␮g E2 (s.c.) or raloxifene (10 mg/kg/d) starting 1wk before stroke ICV injection of FGF-2 (10 ␮g/kg) immediately after stroke 21d infusion of flutamide (5 mg, s.c.) starting 1wk before stroke Infusion of HMF (25 or 50 mg/kg/d, s.c.) for 8d starting 5d before stroke Lnk−/− mice Intrastriatal infusion of meteorin (0.25 ␮g/h) for 14d starting after stroke 90 mg/kg minocycline at reperfusion then 45 mg/kg/d 50 mg/kg/d minocycline Lentiviral overexpression in SVZ (injected 1d before stroke) Intranasal NGF for 6d starting 1d after stroke Activation: Notch-1 activating antibody for 3d (ICV) Inhibition: Jagged-Fc complex or DAPT (0.6 ␮g/d, ICV) for 3d or Notch1 siRNA (ICV) ICV delivery to lateral ventricles Brain surface application Infusion of Smo antagonist cyclopamine (60 pmol/d) for 7d starting 3d post ischaemia SB (300 mg/kg/d, s.c.) for up to 14d starting after ischaemia Testosterone or DHT infusion (5 mg, s.c.) for 21d starting 1wk before stroke TGF-␣ infusion (0.6–2.4 ␮g/d) for 4wk starting 4wk after stroke Trx-1 (3 mg/kg, i.p.) 10 min before reperfusion VPA (100 mg/kg/d, i.p.) for 7d starting 1d after stroke AAV overexpression of VEGF (ICV delivery) Lentiviral overexpression

Mouse tMCAO Neocortical Et-1 injection Mouse tMCAO Neonatal (P7) rat tMCAO Mouse tMCAO

Mouse tMCAO Rat tMCAO

Rat tMCAO Rat pMCAO Mouse pMCAO Rat tMCAO Rat pMCAO Rat tMCAO

Rat pMCAO

Mouse tMCAO

Rat pMCAO Rat tMCAO Striatal Et-1 injection

Kang et al. (2012) Cooke et al. (2011)

Li et al. (2011) Li et al. (2011)

Ahlenius et al. (2012) Wang et al. (2012b)

Rueger et al. (2012) Liu et al. (2013a)

Sun et al. (2013)

Hayon et al. (2013)

Zhang et al. (2014)

Liu et al. (2012) Li et al. (2009a) Shruster et al. (2012)

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deficiency does not alter NPC proliferation in the uninjured brain. After stroke however, LNK expression in SVZ NPCs is increased and Lnk−/− mice exhibit increased NPC proliferation in this context. The ability of LNK to modulate NPC proliferation was corroborated by in vitro analyses revealing that loss of LNK increased NPC proliferation whereas its overexpression reduced NPC proliferation. The impaired proliferation due to LNK was mediated by inhibiting AKT phosphorylation which resulted in reduced insulin-like growth factor 1 (IGF-1) signalling, a factor previously ascribed as a potential mediator of post-ischaemic NPC proliferation (Yan et al., 2006). Ahlenius et al. (2012) postulated that increased LNK expression following stroke could be mediated by increased STAT1/3 signalling in response to stroke-induced elevation in the expression of interleukin-6. Precisely how LNK expression is potentiated specifically after stroke remains to be explored, and the repertoire of responses driven by increased by LNK expression remains unknown. Nevertheless, the finding that elevated expression of the LNK adapter protein after ischaemic stroke attenuates post-ischaemic neurogenesis suggests that blocking increased LNK activity after stroke could be a cogent therapeutic target for enhancing neurogenesis in the SVZ. Further studies to investigate the functional consequences of the LNK-mediated suppression of poststroke NPC proliferation in the SVZ and the consequences of blocking this endogenous response will be required to establish whether blocking LNK activity after stroke could enhance poststroke recovery.

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10.5. CNTF

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pathway mediates adult SVZ NPC proliferation and neuronal fate commitment in normal and ischaemic conditions and that potentiating Notch signalling to increase neurogenesis after ischaemic injury is feasible in both the young and aged rodent brain. Changes in the expression of microRNAs (miRNAs) appear to play an important part in stroke-induced potentiation of Notch signalling. miRNAs are small noncoding RNAs that decrease gene expression through mRNA destabilisation and/or translational repression. Ischaemic stroke has also been found to increase expression of miR-124a in the SVZ following MCAO in the adult rat (Liu et al., 2011). In vitro luciferase assays revealed that miR124a repressed expression of the Notch ligand Jagged-1. Consistent with blockade of Notch signalling, transfecting NPCs with miR124a reduced proliferation, promoted neuronal differentiation and increased the expression of the cyclin-dependent kinase inhibitor p27Kip1(p27), a cell cycle regulator normally suppressed by Notch signalling (Liu et al., 2011). Independent research has demonstrated that p27Kip1 normally acts to inhibit NPC proliferation in both the normal and post-ischaemic brain (Qiu et al., 2009). When p27Kip1 was deleted in mice subject to ischaemic stroke, the proliferation of NPCs and in the generation of new neurons was increased in the dentate gyrus. Collectively, this body of research indicates that stroke alters miR-124 expression in NPCs to potentiate strokeinduced neurogenesis by regulating the expression of Jagged-1 to enable Notch signalling. 10.7. Shh signalling

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The pattern of ciliary neurotrophic factor (CNTF) expression after ischaemic stroke in mice has been demonstrated to closely mirror the kinetics of NPC proliferation in the SVZ (Kang et al., 2012). No stroke-induced potentiation of NPC proliferation was observed in CNTF−/− mice. The mechanism appears to work by inducing expression of the NPC mitogen FGF-2 expression and not by potentiating EGF expression or Notch1 signalling of NPCs in the SVZ (Kang et al., 2012). Examination of the therapeutic benefit of potentiating CNTF expression will provide more definitive data to support the view that pharmacological stimulation of endogenous CNTF expression could potentiate neurogenesis after ischaemia.

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10.6. Notch signalling

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Notch signalling defines a fundamental pathway controlling cell fate acquisition. Studies have demonstrated that Notch signalling pathways play critical roles during the maintenance, proliferation, and differentiation of neural stem cells in the developing brain and in adult germinal zones of the CNS (reviewed by Ables et al., 2011; Pierfelice et al., 2011). Notch signalling is potentiated by focal ischaemia resulting in increased expression of the Notch intracellular signalling moiety NICD and its downstream transcriptional targets, Hes1 and Shh (Wang et al., 2009b). Blocking the Notch1 signalling pathway inhibited ischaemia-induced NPC proliferation suggesting that Notch1 signalling could be an important mediator in driving NPC responsiveness to ischaemia, and these results have been corroborated in vitro (Wang et al., 2009a). Downregulation of Notch1 signalling by Notch1 siRNA or gamma secretase inhibition blocked stroke-induced cell proliferation and potentiated neuronal differentiation of residual progenitor cells without influencing astrocyte production (Wang et al., 2009a). Ageing results in a significant reduction in the expression of Notch1 and Jagged1 in the SVZ. Activating Notch1 signalling pathway in aged ischaemic rats potentiated NPC proliferation which also resulted in reduced infarct volume and improved motor deficits, suggesting that Notch1 signalling modulates the SVZ neurogenesis (Sun et al., 2013). Collectively, these data suggest that the Notch signalling

Sonic hedgehog (Shh) signalling, acting through primary cilia localised on the cell bodies of adult neural stem cells has been demonstrated to play a crucial role in establishing and maintaining the dentate gyrus neurogenic niche and is specifically required for the specification of adult ventral neural stem cells in the SVZ (Breunig et al., 2008; Han et al., 2008; Ihrie et al., 2011). It was recently demonstrated that exposing cultured NPCs to hypoxic conditions in vitro caused increased expression of Shh in NPCs and neurons and potentiated NPC proliferation (Sims et al., 2009). Exogenous Shh also stimulated NPC proliferation in vitro and inhibiting Shh signalling using cyclopamine, a smoothened (Smo) receptor antagonist, inhibited the hypoxia-induced increase in NPC proliferation (Sims et al., 2009). MCAO in mice transiently increased Shh mRNA and Gli1, a transcription factor expressed in response to Shh signalling 0.5 days after ischaemia. Shh protein levels increased in hippocampus 3-fold by day 7 post ischaemia especially in the CA3 and hilar regions and was exclusively expressed in mature neurons. In vivo administration of cyclopamine blocked ischaemia-induced proliferation of NPCs in the SGZ. A novel mediator downstream of Shh signalling has recently been identified to drive the post-ischaemic increase in NPC proliferation in the SVZ. The stroke-induced increase in Shh signalling was found to upregulate the expression of the microRNA cluster miR17-92 (Liu et al., 2013a). The mechanistic link appears to be c-Myc, a transcriptional target of Shh which binds to and activates expression of the miR17-92 cluster. Overexpression of miR17-92 increased NPC proliferation whereas blocking miR17-92 cluster family members (miR-18a or miR-19) inhibited NPC proliferation and promoted cell death (Liu et al., 2013a). Precisely how increased expression of the miR17-92 cluster promotes neurogenesis remains to be established but suppression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been proposed as one potential mechanism (Liu et al., 2013a,b). 10.8. FGF-2 and EGF Fibroblast growth factor-2 and epidermal growth factor were among the earliest mitogens demonstrated to potentiate the

Please cite this article in press as: Merson TD, Bourne JA. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.003

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proliferation of neural stem/progenitor cells in vitro (Reynolds and Weiss, 1992; Richards et al., 1992; Johe et al., 1996). Stimulation of neurogenesis by combined administration of FGF-2 and EGF has also been utilised as a means to potentiate neurogenesis following cerebral ischaemia (Nakatomi et al., 2002; Türeyen et al., 2005). An endogenous neuroprotective role for FGF-2 in limiting infarct volume after ischaemic stroke is suggested by the finding that FGF-2-deficient mice exhibited a 75% reduction in lesion volume after MCAO compared to wild type controls (Kiprianova et al., 2004). However since endogenous FGF-2 is expressed broadly throughout the CNS, this study does not provide direct evidence that aberrant NPC responses underlie increased lesion size; studies modulating FGF signalling specifically within the neurogenic niche will be required to directly address this question. Nevertheless, recent studies into the therapeutic potential of exogenous FGF-2 administration revealed that FGF-2 administration to neonatal rats subject to bilateral common carotid artery (BCCA) occlusion increased proliferation in SVZ and differentiation of these cells into neurons, astrocytes and oligodendrocytes (Jin-Qiao et al., 2009). It has previously been demonstrated that intraventricular infusion of epidermal growth factor (EGF) enhances NPC proliferation in the normal brain. Suspension of EGF in a hyaluranon and methylcellulose hydrogel placed onto cortical surface increased NPC proliferation in both uninjured and stroke-injured brains (Cooke et al., 2011). Combined intraventricular administration of both EGF and FGF-2 to rats subject to global ischaemia also markedly potentiated neurogenesis and stroke-induced increased NPC proliferation in the SVZ and enhanced the recruitment of newborn neurons to the striatum, resulting in increased neuronal density at both 6 and 12 weeks after ischaemia (Yoshikawa et al., 2010). This also translated to improved motor performance which demonstrating that delivery of mitogens resulted in sustained increases in the generation, and integration of SVZ-derived neurons that correlated with improved functional outcome.

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10.9. Growth hormone

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Growth hormone (GH) and its receptor (GH-R) are expressed in the germinal zones of the embryonic and adult CNS (Lobie et al., 1993; Turnley et al., 2002) and play an important role in regulating NPC responsiveness throughout ontogeny. On the one hand, GH has been demonstrated to specifically inhibit neuronal differentiation of NPCs by down-regulating the expression of neurogenin-1 (Ngn1), an activity that is blocked by the activity of suppressor of cytokine signalling 2 (SOCS2) (Turnley et al., 2002). On the other hand, exercise-induced increase in circulating GH has been shown to potentiate the proliferation of SVZ NPCs in aged mice (Blackmore et al., 2009, 2012). The available data suggest that the function of GH signalling in hippocampal progenitors could differ. Acute reduction in circulating GH levels in adulthood specifically reduced the survival of newborn neurons in the dentate gyrus rather than influencing the proliferation or neuronal differentiation of NPCs in the dentate gyrus (Lichtenwalner et al., 2006). In the context of stroke, delivery of exogenous GH into the lateral ventricles following unilateral hypoxic-ischaemic injury in juvenile rats was found to reduce injury-induced neuronal cell death (Scheepens et al., 2001). This neuroprotective effect has been ascribed to the anti-apoptotic activity of insulin-like growth factor 1 (IGF-1), a critical downstream effector of GH signalling (Herrington and Carter-Su, 2001). It will be valid in this context to establish whether exogenous GH also acts directly upon NPCs in the SVZ to potentiate NPC proliferation and the extent to which it modulates neuronal differentiation. Importantly, it has recently been demonstrated that increased NPC proliferation in the ipsilateral SVZ following unilateral hypoxia-ischaemia was associated with heightened GH-R expression by SVZ cells raising the prospect that

GH signalling could be implicated in potentiating post-ischaemic neurogenesis (Christophidis et al., 2009). 10.10. GDNF The glial cell line-derived neurotrophic factor (GDNF) exhibits upregulated expression in a variety of neural cell types in response focal or global cerebral ischaemia (reviewed by Duarte et al., 2012). Although the role of endogenous GDNF remains unclear, exogenous GDNF has been found to exert a neuroprotective effect, in particular by reducing the extent of delayed neuronal cell death in the post-ischaemic brain. A specific role for exogenous GDNF in modulating post-ischaemic neurogenesis has also been demonstrated. Intracerebroventricular infusion of GDNF prior to transient MCAO increased injury-induced NPC proliferation in the ipsilateral dentate gyrus (Dempsey et al., 2003). Intrastriatal infusion of GDNF following ischaemia also promoted striatal neurogenesis at least in part by acting upon SVZ NPCs to promote their proliferation and migration and the survival of new mature neurons (Kobayashi et al., 2006). Most recently, a post-mortem study in patients who died following cerebral infarction has revealed that increases in endogenous GDNF expression were positively correlated with the temporal changes in density of nestin-positive cells in the dentate gyrus and SVZ following ischaemic stroke (Duan et al., 2010). These new data provide a compelling argument for revisiting the role of endogenous GDNF signalling in the regulation of post-ischaemic neurogenesis. 10.11. Neurotrophic factors Nerve growth factor (NGF) was initially discovered as a neurotrophic factor that promotes survival and differentiation of developing neurons within the peripheral nervous system and was subsequently found to exert similar functions in the CNS (reviewed by Sofroniew et al., 2001). In addition to classical neurotrophic activity in the developing nervous system, endogenous NGF exerts a multitude of functions on various neuronal and non-neuronal cell types in the adult CNS both under normal physiological conditions and in response to CNS injury, acting to promote neuroprotection and neural repair (Sofroniew et al., 2001). More recently, a specific function for NGF in promoting the survival of newly generated neurons has been described. In the context of ischaemic brain injury it has been demonstrated that intranasal delivery of NGF to rats subject to unilateral MCAO improved the survival of newly generated neurons in ipsilateral striatum and SVZ without modulating cell proliferation (Zhu et al., 2011a,b). Broad ranging effects of the neurotrophic factor mimetic cerebrolysin have recently been reported in a rat model of embolic MCAO (Zhang et al., 2010). Daily intraperitoneal injection of cerebrolysin for 21 days starting 24 h after MCAO increased the density of proliferating NPCs and neuroblasts in the ipsilateral SVZ and ischaemic boundary when examined 28 days after stroke. Importantly, at doses of cerebrolysin that induced robust NPC proliferation but did not alter the infarct volume there was neurological benefit indicated by improved recovery after post stroke. In vitro analysis revealed that cerebrolysin dose-dependently increased NPC proliferation, migration and production of TuJ1immunoreactive immature neurons and that these effects were blocked by inhibiting PI3K/Akt signalling (Zhang et al., 2010). Meteorin is a neurotrophic factor that is highly expressed in NPCs in the developing brain and promotes migration of neuroblasts from SVZ explants and reduces NMDA-induced apoptotic cell death in vitro. Meteorin expression is increased in striatum after stroke and infusion of recombinant meteorin potentiates cell proliferation in the SVZ and enhances migration of neuroblasts and their subsequent maturation in striatum (Wang et al., 2012b). This

Please cite this article in press as: Merson TD, Bourne JA. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.003

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recent observation is interesting given the previous description of meteorin in the regulation of glial cell differentiation (Nishino et al., 2004).

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10.12. Ephrin-B3

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Eph receptor/ephrin signalling is a critical mediator of many developmental processes including cell migration, axon guidance, cell segregation and positioning, tissue boundary formation, and vascular and skeletal morphogenesis (reviewed by Klein, 2012). Direct cell–cell contact is required for binding to occur between the Eph receptor tyrosine kinase and ephrin ligand, resulting in either unidirectional or bidirectional signalling from both the ligand and receptor (reviewed by Wilkinson, 2001). Several ephrins and their Eph receptors have been implicated in the regulation of diverse aspects of neural stem/progenitor cell function in adult neurogenic niches. These functions include regulating NPC proliferation, apoptosis, differentiation, migration and cellular polarity as well as maintaining neural stem cells in an undifferentatied state (Depaepe et al., 2005; Holmberg et al., 2005; Katakowski et al., 2005; Chumley et al., 2007; Qiu et al., 2008; Furne et al., 2009; Theus et al., 2010). Recent research highlights a specific role for ephrin-B3 in modulating NPC responsiveness following ischaemic stroke. Previous work has demonstrated that, under normal physiological conditions, ephrin-B3 and its receptor EphB1 function cooperatively to control NPC migration in the dentate gyrus, promote NPC survival in the SVZ and restrict NPC proliferation in both regions (Ricard et al., 2006; Chumley et al., 2007). More recently it has been demonstrated that ephrin-B3 signalling could be an important therapeutic target for the treatment of stroke (Doeppner et al., 2011). Specifically, MCAO in ephrin-B3 knockout mice resulted in enhanced post-ischaemic neurogenesis around the ischaemic lesion that was accompanied by increased cell death and worsened functional recovery compared to wild-type controls. Increased caspase-3 activation appeared to be a critical determinant of increased infarct volume in ephrin-B3 knockout mice since injury volume in knockout mice was reduced to wild-type levels following pharmacological blockade of caspase-3 activity (Doeppner et al., 2011). Future studies will be required to establish whether caspase3-dependent activation of STAT1 in the post-ischaemic brain is responsible for the increased ischaemic injury. These data suggest that selective blocking of ephrin-B3 activity in NPCs could be beneficial to promote neurogenesis and illustrates the point that the extent of neurogenesis and neurological recovery are not necessarily concordant.

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10.13. ERK signalling

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The Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) signalling cascade couples signals from cell surface receptors to transcription factors, which regulate gene expression. Consequences of Ras/Raf/MEK/ERK signalling vary according to the specific stimulus and cell type, resulting in either blocking or potentiating apoptosis or cell cycle progression (Chang et al., 2003). In the context of post-ischaemic neurogenesis, a number of promising agents have recently been demonstrated to exert their effects at least in part by potentiating Ras/Raf/MEK/ERK signalling in NPCs or newborn neurons. For example, recombinant human thioredoxin1, a small protein that exhibits antioxidative, anti-apoptotic and pro-proliferative activities has recently been demonstrated to potentiate hippocampal neurogenesis following ischaemic stroke (Tian et al., 2014). In adult mice subjected to transient global cerebral ischaemia, infusion of rhTrx-1 before reperfusion enhanced NPC proliferation in the dentate gyrus, increasing the density of neuroblasts and mature neurons in this structure. Treatment also

11

afforded cognitive benefits in a spatial memory task. Mechanistically, the effects of rhTrx-1 appeared to act by potentiating ERK1/2 phosphorylation, effects that were abrogated in vitro by treatment of NPCs with the ERK inhibitor U0126 (Tian et al., 2014). ERK phosphorylation has also been implicated in the proneurogenic activity of the citrus flavonoid heptamethoxyflavone (HMF). Administration of HMF to mice subject to transient global cerebral ischaemia induced phosphorylation of both ERK1/2 and its downstream target cAMP response element-binding protein (CREB) (Okuyama et al., 2012). Expression of BDNF, a transcriptional target of phospho-CREB was elevated in GFAP-positive cells in the dentate gyrus, and this was associated with an increase in the density of doublecortin-positive cells in both the SVZ and dentate gyrus (Okuyama et al., 2012). Under normal physiological conditions, it has been clearly demonstrated that exogenous BDNF increases the generation of newborn neurons in vivo (Zigova et al., 1998; Benraiss et al., 2001; Pencea et al., 2001; Lee et al., 2002; Chmielnicki et al., 2004). Furthermore, BDNF directly stimulates neuronal differentiation of adult hippocampal progenitors (Bull and Bartlett, 2005) and greatly enhances neuronal differentiation in adult SVZ-derived NPCs by binding the pan-neurotrophin receptor p75 (p75NTR) (Young et al., 2007). The role of exogenous BDNF signalling in mediating the increase in neurogenesis after stroke is less clear. On the one hand, consistent with the role of BDNF in the normal adult brain (Young et al., 2007), it has been reported that antagonising the normal increase in BDNF observed following hypoxic-ischaemic injury using anti-BDNF neutralising antibodies attenuated post-ischaemic increase in hippocampal neurogenesis (Zhu et al., 2010). On the other hand, viral-mediated overexpression of BDNF in the hippocampus suppressed ischaemia-induced neurogenesis (Larsson et al., 2002) whereas blocking the activity of endogenous BDNF by intraventricular infusion of the BDNF decoy receptor TrkB-Fc after cerebral ischaemia was found to potentiate the differentiation of newborn neurons (Gustafsson et al., 2003). Further studies will be required to establish whether the observed increase in endogenous BDNF expression observed following HMG administration potentiates or abrogates the generation of mature neurons after cerebral ischaemia.

11. Epigenetic modifiers Various chromatin regulatory factors and their inhibitors have recently been investigated for their potential as therapeutic agents for the treatment of ischaemic stroke (reviewed by Shein and Shohami, 2011). In addition to their potential to mitigate against ischaemic injury directly, chromatin-modifying agents could be important mediators of ischaemia-induced neurogenesis since many chromatin remodelling factors have been demonstrated to play important roles in neural stem/progenitor cells (reviewed by Qureshi and Mehler, 2011). Notably, two recent studies have identified that the histone deacetylase inhibitors (HDACs) could exert beneficial effects in the post-ischaemic brain at least in part by potentiating neurogenesis. In MCAO challenged rats administration of valproic acid (VPA) a pan HDAC inhibitor, significantly improved neurological outcome for up to one month after treatment (Liu et al., 2012). VPA treatment increased both the survival and regeneration of oligodendrocytes, resulting in a concomitant increase in the density of myelinated axons in the ischaemic boundary. VPA treatment also increased levels of acetylated histone-H4 in neuroblasts and increased the number of new neurons in the ischaemic boundary (Liu et al., 2012). Similar observations have been made using the HDAC inhibitor sodium butyrate which was found to stimulate NPC proliferation and enhance neuron production in the SVZ and dentate gyrus of rats subject to permanent MCAO (Kim et al., 2009b). Sodium butyrate also increased nestin and GFAP protein levels in

Please cite this article in press as: Merson TD, Bourne JA. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.003

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the SVZ and striatum. Ischaemia was associated with reduced levels of acetylated histone-H3 in neurons within the dentate gyrus and reduced levels of BDNF and phospho-CREB in the SVZ, effects that were reversed by sodium butyrate treatment. Blocking BDNF signalling by intraventricular infusion of the TrkB receptor antagonist K252a prior to MCAO markedly reduced the pro-neurogenic effects of sodium butyrate (Kim et al., 2009b). Collectively, these data suggest that potentiation of neurogenesis and neuronal differentiation by sodium butyrate treatment after ischaemic stroke are mediated by enhanced BDNF-TrkB signalling. Examination of the effects of HDAC treatment upon the chromatin structure around BDNF gene regulatory elements would further clarify this mechanism.

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12. Future studies and clinical translation

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Research over the last 5 years has significantly advanced our understanding of the cellular and molecular mechanisms underlying ischaemia-induced neurogenesis. Of particular note is the mechanistic link between processes regulating angiogenesis and neurogenesis, highlighting the important link between these two regenerative processes following ischaemic injury. It is also becoming increasingly clear that potentiating neurogenesis following experimental ischaemic stroke reduces infarct volume and provides clinical benefit in rodent models. An important avenue for future research will be to establish which aspects of the neurogenic response are important: the provision trophic support/neuroprotection, facilitating the plasticity of surviving neuronal circuits and/or for generating functionally integrated neurons within the post-ischaemic brain. Clearly, the notion that neurogenesis provides clinical benefit merely by the provision of newborn neurons to the ischaemic penumbra must be reviewed in light of recent ablation studies indicating that NPCs could provide neuroprotection in the acute period prior to the generation of new neurons. Dissecting which aspects of the neurogenic response are beneficial will guide the development of new interventions designed to potentiate the neurogenic response in patients following ischaemic stroke. Before novel pro-neurogenic interventions can be tested in the clinic, it is important to reflect on the history of research translation in ischaemic stroke. In the area of neuroprotection, translation from rodent studies to therapeutic use has failed for well over 1000 experimental interventions (O’Collins et al., 2006; Sacchetti, 2008). The importance of scientific rigour and appropriate choice of animal models for pre-clinical testing of putative agents has recently been highlighted (Tymianski, 2010; Neuhaus et al., 2014). Recent advances in the area of neuroprotection using the PSD-95 inhibitor Tat-NR2B9c has highlighted the importance of pre-clinical testing in cynomolgus macaques, a gyrencephalic nonhuman primate model (Cook et al., 2012a,b). Preclinical testing of Tat-NR2B9c proved to accurately predict beneficial outcome in a subsequent human clinical trial (Hill et al., 2012), reopening the quest for neuroprotective therapies for ischaemic stroke in humans (Kaste, 2012). Nonhuman primate models of reversible and permanent ischaemic stroke offer distinct advantages over non-primate models due to similarities in cerebral anatomy and circulatory patterns (Teo et al., 2012). Although animal models in species other than nonhuman primates are important to elucidate the basis of the physiological and mechanistic responses to injury, these models offer poor translation of experimental treatment strategies to clinical applications. Radiocarbon 14 C-based birthdating of neuronal nuclei isolated form the cerebral cortex of stroke-affected patients has failed to find evidence of any measurable level of new neuronal production after stroke (Huttner et al., 2014). On the other hand, the same approach has demonstrated that significant levels of neurogenesis occur within the normal human striatum (Ernst et al.,

2014). These recent findings highlight the significant structural and functional differences that exist between rodent and human brains, drawing into focus the critical need to establish better pre-clinical models of stroke. To this end, a novel model of ischaemic stroke reflecting transient occlusion of the posterior cerebral artery of the neonatal or adult marmoset monkey has recently been described (Teo and Bourne, 2014). This model provides a highly reproducible and survivable model of focal ischaemia which demonstrates similar downstream anatomical and cellular pathology to the human. The model also has the distinct advantage that focal injury specifically affects the visual cortex which will allow for qualitative and quantitative assessments of functional visual deficits following PCA strokes. Furthermore, it is a suitable laboratory species in which to examine changes at the cellular and molecular level and trial novel therapeutics. The marmoset is also amenable to in vitro examination of neocortical NPC responses, a first in terms of the nonhuman primates (Homman-Ludiye et al., 2012) and we have been able to readily propagate NPCs from the adult SVZ and hippocampus of this species (unpublished results, Merson and Bourne). Further developments of nonhuman primate models of ischaemic stroke are essential for the on-going investigation of post-ischaemic neurogenesis as well as to understand the functional and behavioural consequences of these responses following ischaemic stroke. Pre-clinical examination of novel therapeutic strategies targeting post-ischaemic neurogenesis in suitable nonhuman primate models will provide the greatest potential for translating findings for the treatment of ischaemic stroke in humans. Acknowledgements The Florey Institute of Neuroscience and Mental Health acknowledges the support from the Victorian Government’s Oper- Q4 ational Infrastructure Support Grant. The Australian Regenerative Q5 Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. JAB & TDM are supported by National Health and Medical Research Council Project Grants and Stem Cells Australia, an Australian Research Council Special Research Initiative in Stem Cell Science. References Ables JL, Breunig JJ, Eisch AJ, Rakic P. Not(ch) just development: notch signalling in the adult brain. Nat Rev Neurosci 2011;12(May (5)):269–83. Ahlenius H, Devaraju K, Monni E, Oki K, Wattananit S, Darsalia V, et al. Adaptor protein LNK is a negative regulator of brain neural stem cell proliferation after stroke. J Neurosci 2012;32(April (15)):5151–64. Ahmed AI, Shtaya AB, Zaben MJ, Owens EV, Kiecker C, Gray WP. Endogenous GFAPpositive neural stem/progenitor cells in the postnatal mouse cortex are activated following traumatic brain injury. J Neurotrauma 2012;29(March (5)):828–42. Alipanahzadeh H, Soleimani M, Soleimani Asl S, Pourheydar B, Nikkhah A, Mehdizadeh M. Transforming growth factor-␣ improves memory impairment and neurogenesis following ischemia reperfusion. Cell J 2013;16.(October (3)). Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002;8(September (9)):963–70. Banz Y, Rieben R. Role of complement and perspectives for intervention in ischemiareperfusion damage. Ann Med 2012;44(May (3)):205–17. Barkho BZ, Munoz AE, Li X, Li L, Cunningham LA, Zhao X. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells 2008;26(December (12)):3139–49. Beck H, Plate KH. Angiogenesis after cerebral ischemia. Acta Neuropathol 2009;117(May (5)):481–96. Bendel O, Bueters T, von Euler M, Ove Ogren S, Sandin J, von Euler G. Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory. J Cereb Blood Flow Metab 2005;25(December (12)):1586–95. Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, et al. Protective astrogenesis from the SVZ niche after injury is controlled by notch modulator Thbs4. Nature 2013;497(May (7449)):369–73. Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA. Adenoviral brainderived neurotrophic factor induces both neostriatal and olfactory neuronal

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Please cite this article in press as: Merson TD, Bourne JA. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.003

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Endogenous neurogenesis following ischaemic brain injury: insights for therapeutic strategies.

Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acut...
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