Therapeutic application of neural stem cells and adult neurogenesis for neurodegenerative disorders: regeneration and beyond.

NIH Public Access Author Manuscript Eur J Neurodegener Dis. Author manuscript; available in PMC 2015 February 25.

NIH-PA Author Manuscript

Published in final edited form as: Eur J Neurodegener Dis. 2012 ; 1(3): 335–351.

Therapeutic application of neural stem cells and adult neurogenesis for neurodegenerative disorders: regeneration and beyond Sarah E. Latchney and Amelia J. Eisch* Department of Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 74309-9070, USA

SUMMARY


With the growth of the aging population and increasing life expectancy, the diagnosis of agerelated neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer’s, Huntington’s, and Parkinson’s diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-ofconcept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the “traditional” view of neurodegeneration – overt cell loss – for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult neurogenesis, and a better understanding of the pathological trajectory of each neurodegenerative disease.


Keywords neurodegeneration; hippocampus; subgranular zone; subventricular zone

*

Corresponding author: [email protected], Telephone: (214)-648-5549, Fax: (214) 645-9549.

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INTRODUCTION NIH-PA Author Manuscript

With the unprecedented growth of the aging population and increasing life expectancy, agerelated neurological diseases like Alzheimer’s, Parkinson’s, and Huntington’s diseases (AD, PD, HD) are predicted to increase 12% worldwide by 2030. The diagnoses of AD alone are projected to increase 35% from 2015 to 2030 (World Health Organization 2006). This rise in neurodegenerative diseases poses a significant global health concern and socioeconomic burden. Individuals diagnosed with a neurodegenerative disease often exhibit a combination of cognitive and motor dysfunction, neuropsychiatric disturbances, and behavioral issues that place a heavy strain on the individual and their family. Basic and clinical research has unraveled many of the pathological hallmarks and biological underpinnings of these diseases. In contrast, the development of disease-modifying therapies has been slower. There are currently no widely available treatments to prevent or slow the progression of AD, PD, or HD (World Health Organization 2006), emphasizing the need for improved and novel therapeutic approaches for these disorders.


One commonality among these neurodegenerative diseases is that their pathological trajectories either promote or are the result of extensive neuronal cell loss, leading to irreversible tissue damage and ultimately neurological dysfunction. Because of the substantial loss of neurons, it is reasonable that one therapeutic strategy explored focuses on replacing the cells that are lost or damaged (Madhavan and Collier 2010). This approach is spurred by the hope that replaced cells would functionally integrate in the diseased region and minimally ameliorate neurological dysfunction. Fueling enthusiasm for such a cell replacement strategy was the discovery that neural stem cells reside in niche-privileged neurogenic regions of the adult mammalian brain (Ming and Song 2011) and are capable of integrating into the local neural circuitry (Zhao et al. 2008). Therefore, the last 2 decades have seen a tremendous rise in the number of experimental approaches hinging on the principle of using NSPCs as a cell transplantation tool and exploiting the process of adult neurogenesis to assist in brain repair (Arias-Carrion et al. 2007; Martino et al. 2011; De Feo et al. 2012).


Many studies have demonstrated the proof-of-principle that NSPCs can be used to not only replace cells that are lost, but also that their progeny can become functionally integrated and restore neurological function (Bjorklund et al. 2003; Mendez et al. 2005; Arias-Carrion et al. 2006; 2008). For example, patients with PD that received fetal dopaminergic cell transplants in the striatum and substantia nigra had improved neurological function without motor complications (Mendez et al. 2005). However, due to the complexity of these diseases, it is probably not surprising that current cell transplantation strategies have had mixed success in restoring neurological function and preventing the reoccurrence of disease cytopathology (Li et al. 2008; Hedlund and Perlmann 2009; Li et al. 2010; Politis et al. 2011; 2012). This is evident in patients receiving transplanted dopaminergic (DA) neurons, in which post mortem studies have revealed histopathological changes characteristic of PD, including loss of pigmented neurons and accumulation of α-synuclein in Lewy bodies of surviving neurons (Li et al. 2008; 2010). Furthermore, it has become clear that neurodegeneration involves much more than solely the loss of neurons, and that symptoms can appear even before overt neuron loss is evident (Nguyen et al. 2006). Eur J Neurodegener Dis. Author manuscript; available in PMC 2015 February 25.

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To maintain pace with the evolving appreciation of neurodegeneration – it is far more than just overt neuron loss – and with the increasing knowledge about both the disease processes and adult neurogenesis, here we synthesize recent literature to highlight new thinking about how the power of NSPCs can be harnessed for treating AD, PD, and HD. We discuss how neurodegeneration is traditionally defined – overt cell loss – and the challenges this definition poses when considering cell transplantation as a strategy to treat neurodegenerative diseases. We propose alternative strategies centering on the idea of finetuning the neurogenic capacity of endogenous adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. To address these topics, we discuss: 1) NSPCs and adult neurogenesis and how they relate to neurodegenerative diseases; 2) the current perspective on cell transplantation strategies, their progress and limitations; and 3) how we can use the increasing knowledge base on neurogenesis to drive future strategies in exploiting NSPCs to replace, repair, and regenerate the brain.

The problem: diverse pathologies and pathology timelines in AD, PD, and HD NIH-PA Author Manuscript

Simply stated, the term neurodegeneration describes a chronic process in which numerous cell types are damaged and/or destroyed. However, central to this review is the fact that multiple biological processes are affected during the trajectory of age-related neurological diseases, and that overt neuronal loss or dysfunction may be the endpoint of these disorders and not the cause. It is important to consider the diverse pathologies and timelines of neurodegenerative disorders when envisioning how NSPCs can be harnessed to improve these conditions. While an exhaustive analysis of the neuropathologies of AD, HD, and PD is outside the scope of this review (Caselli et al. 2006; Imarisio et al. 2008; Hedlund and Perlmann 2009), an overview of the primary pathologies and general pathological trajectory of these disorders helps put into context the therapeutic potential of NSPCs that is described in the next section. To this end, Table 1 depicts an overview of key pathological hallmarks and cytopathologies, and the relative timeline of pathological events that occur in AD, PD, and HD. The most salient points of Table 1 are summarized in the subsequent paragraphs.


AD is the most common form of age-related dementia. β-amyloid plaques and neurofibrillary tangles are microscopic hallmarks in brains of those afflicted by AD (Caselli et al. 2006; Lazarov and Marr 2010). Amyloid plaques are dense, insoluble, extracellular plaques that result from the accumulation of aggregated amyloid precursor protein (APP). Intracellular neurofibrillary tangles result from a hyperphosphorylated form of the microtubule-associated protein tau. The build up of aggregated APP and tau proteins interferes with many cellular functions, and is believed to contribute to the substantial loss of neurons and synapses in the cortex and hippocampus. In regards to the pathological sequence of events, many patients afflicted with AD develop mild cognitive symptoms before there is detectable neuronal and synaptic loss. This indicates that additional biological processes other than overt neuronal cell loss may be responsible for the onset of the AD pathological cascade. This concept is supported by the linking of AD to insulin resistance (Accardi et al. 2012) or dysfunctional vasculature (Verghese et al. 2011), and encourages a

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broader investigation of the most “upstream cause” of a disorder rather than the endpoint of neuronal loss.


PD is characterized by a gradual loss of DA secreting neurons in the substantia nigra pars compacta (SNpc), a midbrain region that projects DA terminals to the striatum and forebrain (Hedlund and Perlmann 2009). The accumulation of α-synuclein deposits in Lewy bodies of the SN is also a pathological indicator of DAergic damage in the nigrostriatal pathway. The steady loss of SNpc DA neurons leads to severe motor impairments, including tremor, rigidity, bradykinesia, and postural instability. However, as with most neurodegenerative disorders, the pathology in PD is not restricted to a sole set of neurons. For example, PD patients also develop non-motor neuropsychiatric symptoms, such as disruptions in sleep, mood, cognition, depression, and anxiety (Kano et al. 2011; Politis et al. 2012). These nonmotor symptoms are hypothesized to be due to loss of or dysfunction in other monoaminergic (norepinephrine, NE) and indolaminergic cells (serotonin, 5HT) (Kano et al. 2011; Politis et al. 2012). Interestingly, the majority of SNpc DA neurons are lost before patients develop neurological impairments. This underscores that PD has a very distinct disease trajectory from AD, as AD symptoms appear prior to significant loss of neurons.


Like PD, HD is a neurodegenerative disease characterized by movement abnormalities, cognitive impairments, and affective disturbances. However, the pathology of HD differs in that it is a result of the heritable expansion and aggregation of CAG trinucleotide repeats within the coding region of the huntingtin gene (htt). This triggers the progressive loss of medium spiny GABAergic neurons in the striatum. Degeneration of cortical and hippocampal neurons are also observed and are thought to contribute to the cognitive deficits. With HD, it remains unclear whether the loss of GABAergic cells in the SN leads to the motor and cognitive impairments, or if the neurological impairments manifest before there is significant neuron loss.


This main point of this brief disease pathology overview is that while AD, PD, and HD are all marked by neuronal loss, each disease is accompanied by a distinct pathology and timeline of pathological events, as summarized in Table 1. Given this diversity, what role might NSPCs have in helping replace lost neurons? And given that overt neuron loss in many cases is the endpoint – but not the direct cause of symptomatology – what role might NSPCs play in delaying or halting the pathological trajectory in these disorders? In other words, might NSPCs help in ways beyond merely providing a new source of the degenerating neurons?

A solution: new neurons to the rescue? Beginning in the 1990s, exogenous and endogenous NSPCs were heralded as novel tools for cell transplantation and brain repair (Eriksson et al. 1998). This enthusiasm began with the discovery of adult neurogenesis 50 years ago (Altman 1962), and was fueled by the growing appreciation that the adult mammalian brain gives rise to new neurons throughout life (Suh et al. 2009; Ming and Song 2011; Toni and Sultan 2011). As NSPCs have the potential to be useful in treating neurodegenerative disorders, here we provide a brief overview of key


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principles of adult neurogenesis, including the role of NSPCs in the dynamic nature of adult neurogenesis in both the healthy brain and in neurodegenerative disorders.


Neurogenesis in the healthy brain The discovery of ongoing neurogenesis in the adult brain introduced a new form of neuroplasticity that could – in theory – sustain many of the biological processes that are lost or damaged in neurodegenerative disorders. As indicated in Figure 1, there are two main neurogenic areas in the adult mammalian brain: the subgranular zone (SGZ) of the hippocampal dentate gyrus, and the subventricular zone (SVZ) lining the lateral ventricles. The SGZ gives rise to new dentate gyrus glutamatergic cells, while the SVZ cells give rise to inhibitory GABAergic olfactory bulb interneurons (Zhao et al. 2008). To understand how NSPCs and adult neurogenesis might help treat neurodegenerative disorders, it is helpful to briefly review the process of neurogenesis in each of these regions.

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The SGZ – as a neurogenic niche – hosts cell types of varying degrees of neuronal maturity, referred to as “stages” of neurogenesis (Kempermann et al. 2004). These cell types and stages are shown in simplified form in Figure 1. Type-1 cells are the putative stem cell of the hippocampal dentate gyrus, presenting a radial glial-like morphology. Type-1 cells are closely related to astrocytes (Wang and Bordey 2008), but have a very limited capacity to proliferate, and are relatively resistant to environmental and physiological stimuli. Thus, Type-1 cells are commonly referred to as quiescent neural progenitors. When they do divide, Type-1 cells give rise to rapidly dividing progenitor cells, known as Type-2 cells. Type-2 progenitor cells have a small round cell body located in the SGZ but lack radial processes. Since they rapidly proliferate, Type-2 cells make up the majority of the neural progenitor cell pool. A large proportion of cells die via apoptosis during the first few days after they are generated (Cooper-Kuhn and Kuhn 2002; Sierra et al. 2010). However, if they survive, Type-2 cells and their progeny eventually differentiate into Type-3 immature neurons. Once they become dentate gyrus granule cell neurons, they integrate into hippocampal networks encoding spatial memory and pattern separation (Kee et al. 2007; Clelland et al. 2009; Stone et al. 2011) and, after a period of additional maturation, become physiologically indistinguishable from existing granule cell neurons (van Praag et al. 2002). A major characteristic of hippocampal neurogenesis is the limited distance that the adult-generated cells migrate; cells generated in the SGZ migrate only a short distance to become glutamatergic granule cells and contribute to the mossy fiber projection from the dentate gyrus to other hippocampal regions. This limited migration is likely due to both intrinsic and extrinsic cues, but also due to the physical barriers – like the hippocampal fissure – that circumscribe the dentate gyrus and separate it from the rest of the hippocampus, like CA1 (Figure 1). NSPCs cells also reside in the SVZ that lines the walls of the lateral ventricles (Figure 1; Lledo and Saghatelyan 2005; Lledo et al. 2006). Transiently-amplifying precursors, termed Type C cells, are born in the SVZ and, analogous to Type-2 cells in the dentate gyrus, are the most mitotically active pool of progenitors. These rapidly dividing cells then differentiate into Type A neuroblasts, which then organize themselves into chains, surrounded by astrocytes (Type B cells). Unlike the SGZ, the neuroblasts migrate a


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relatively long distance towards the olfactory bulb along a defined pathway called the rostral migratory stream (RMS). Once inside the olfactory bulb, migrating neuroblasts detach from the chains and migrate radially to their final positions in the granule and glomerular layers. They eventually differentiate into local interneurons and participate in the local neural network where they contribute to key olfactory functions, including olfactory response to chemical cues, olfactory memory, and conspecific interactions (Lazarini and Lledo 2011; Wei et al. 2011; Kageyama et al. 2012). The RMS migration is an important characteristic of SVZ neurogenesis. As discussed below, this opens the possibility of luring neuroblasts into adjacent regions, like the striatum, which may benefit from a new potential source of neurons under diseased conditions. Outside of the SGZ and SVZ, evidence suggests that NSPCs may exist in other brain regions, such as the SN, striatum, or cortex as indicated in Figure 1 (Abrous et al. 2005; Ming and Song 2011). These additional “nests” of NSPCs are poorly understood, but are a promising new source of neurons or other supporting cells. Examination of the SGZ, SVZ, and these additional regions hosting NSPCs is critical for shedding light on intrinsic and extrinsic factors that could be exploited in our efforts to harness these multipotent cells for cell replacement, repair, and regeneration therapies.


Neurogenesis during conditions of neurodegeneration


Neurogenesis is a highly dynamic process in which cells in various stages of maturity are highly responsive to physiological and environmental stimuli (Ming and Song 2011). In view of this novel form of adult neuroplasticity and the sensitivity of adult neurogenic regions to various stimuli, it has been hypothesized that the SGZ and SVZ are altered during the pathogenesis of disease, leading to abnormal neurogenesis (Winner et al. 2011). Abnormal neurogenesis, in turn, may exacerbate neuropathology and contribute to the neurological symptoms observed in patients (Winner et al. 2011). The literature on disrupted neurogenesis in the brains of humans diagnosed with AD, PD, and HD and in related animal models is extensive, is thoroughly reviewed elsewhere (Lazarov and Marr 2010; Mu and Gage 2011; Winner et al. 2011), and thus will not be thoroughly discussed here. However, the human literature highlights the difficulties of extrapolating information from post mortem studies in order to guide basic and translational research. For example, patients with senile AD are reported to have enhanced neurogenesis, as demonstrated by an increase in doublecortin (DCX), polysialylated-neural cell adhesion molecule (PSA-NCAM), and NeuroD expression (Jin et al. 2004). However, this was not seen in the brains of younger, presenile AD patients, which instead are reported to have increased glial and vascularassociated markers (Boekhoorn et al. 2006). Animal models of AD also show this variability in alterations in neurogenesis, with some showing decreased and some showing increased SGZ neurogenesis (German and Eisch 2004). This variability could be due to the dynamic and complex nature of AD, for example with ectopic granule neurogenesis providing an additional way to reconcile the differing results in the field (Donovan et al. 2006). In other words, sole consideration of human post mortem studies makes it difficult to establish if an upregulation in neurogenesis is neuroprotective and promotes functional recovery, or if it signifies a pathological reorganization and restructuring of the local neural network. Furthermore, even if the increase in neurogenesis in human post mortem tissue was


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neuroprotective and promotes functional recovery, it is unclear if the increase in cell generation is robust enough to be of therapeutic value. Because it is difficult to extrapolate functional interpretations of these human studies, below we review a few seminal and recent findings from basic research to provide an updated view of how neurogenesis is altered in neurodegeneration with a focus on animal models.


In support of the theory that disrupted neurogenesis and neurodegeneration are interrelated, key molecular players involved in etiology and pathology of AD, PD, and HD – including presenilin-1 (PSEN1), APP, tau, α-synuclein, and htt – are also physiologically involved in modulating adult neurogenesis. This is reflected in transgenic animals used to model AD, PD, and HD in which neurogenesis is compromised and precedes neuronal loss. For example, triple transgenic mice (3x Tg-AD) harboring three mutant genes (APP, PSEN1, and tau) develop hippocampal tau-like pathology, β-amyloid plaque deposition, and neurological deficits, and have decreased proliferation associated with the presence of βamyloid plaques and more β-amyloid-containing hippocampal neurons (Rodriguez et al. 2008). Hippocampal neurogenesis is also impaired in transgenic-AD mice harboring single or double mutations of PSEN1 or APP, including reduced progenitor cell proliferation, survival, and neuronal differentiation (Wang et al. 2004; Wen et al. 2004; Donovan et al. 2006; Choi et al. 2008; Ermini et al. 2008; Demars et al. 2010; Veeraraghavalu et al. 2010). Tau protein – a microtubule-associated protein that stabilizes neuronal axons in the hippocampus under physiological conditions – is reduced in AD mouse models that also have reduced neurogenesis (Llorens-Martin et al. 2012). As alluded to above, increased neurogenesis is also observed in mouse models of AD, reflecting the complexity and bidirectionality that AD may have on the adult hippocampus (Haughey et al. 2002; Chen et al. 2008; Mirochnic et al. 2009). Regardless of their effects on neurogenesis, these studies indicate that although mutant or aggregated forms of APP, presenilin, or tau molecules contribute to the pathogenesis of AD, they are also crucial for modulating hippocampal neurogenesis in non-pathological processes.


Alterations in SGZ and SVZ neurogenesis manifest in animal models of PD and HD as well. Mice expressing mutant A53T, a mutation in the human α-synuclein gene that leads to early onset of PD, have impaired hippocampal neurogenesis (Winner et al. 2004). SVZ neurogenesis is also decreased in experimental models of DA depletion (Baker et al. 2004; Hoglinger et al. 2004; Winner et al. 2008b), which can produce fewer adult-generated neurons in the olfactory bulb (Marxreiter et al. 2009). In the case of HD, two different transgenic mouse models expressing exon 1 of the human HD gene carrying highly expanded CAG repeats develop many features of HD including involuntary stereotypic movements, tremor, and epileptic seizures (Mangiarini et al. 1996). Along with the neurological symptoms, both HD mouse models demonstrate decreased progenitor proliferation and fewer mature neurons in the hippocampus (Lazic et al. 2004; Gil et al. 2005; Phillips et al. 2005; Lazic et al. 2006). Moreover, mutant rats that have 51 CAG repeats – more closely mimicking HD – have fewer amplifying progenitors and more quiescent Type-1 stem cell cells (von Horsten et al. 2003). However, in the SVZ of the R6/2 mouse model of HD, cell proliferation is enhanced (Batista et al. 2006; Cho et al. 2007),


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further demonstrating the diverse and complex effects neurodegenerative diseases may have on adult neurogenesis.


Neurogenesis and neurodegeneration at the crossroads


This select review of basic research highlights a compelling connection between neurodegeneration and altered adult neurogenesis. However, it remains to be determined if and how impaired adult neurogenesis contributes to the cognitive and emotional alterations observed in these neurodegenerative diseases. Nevertheless, the dual roles that APP, tau, αsynuclein, and other molecules play in healthy and degenerating neurons (Lazarov and Marr 2010; Winner et al. 2011) support the premise that returning neurogenesis to healthy levels in diseased-affected brain regions may be a means to induce neuroregeneration and to restore neurological function. Furthermore, the timing of neurogenic changes in the dentate gyrus and SVZ closely parallel the appearance of affective symptoms, such as depression and anxiety, which arise early in the disease progression. This raises the important consideration that stimulating or normalizing neurogenesis may help ameliorate symptoms, even if they do not address the overt neuron loss characterizing each disorder. It is also interesting to note that in diseases like AD and HD, neurogenic impairments in some transgenic mouse models may occur long before the appearance of disease-related pathologies (Nguyen et al. 2006; Demars et al. 2010), supporting the proposition that altered neurogenesis may be a contributing factor for neurological symptoms rather than a direct result of neuronal cell loss. It is therefore important to understand how NSPC generation is altered in neurodegenerative diseases, but also the specific timeline of when NSPC generation is altered in neurodegenerative diseases. This is crucial to our ability to fine-tune neurogenesis, reverse disease-specific pathologies, and induce cell regeneration in specific diseases.

Harnessing NSPCs for treatment of neurodegenerative disorders: neuroreplacement and neuroprotection


When considering therapeutic strategies for neurodegenerative diseases, a major and reasonable proposition has been to replace disease-specific cell types that are lost during disease progression (Martino et al. 2011; De Feo et al. 2012). NSPC transplantation was regarded as a logical approach because this method addresses the main challenges of all neurodegenerative diseases: substituting cells that are lost with newly differentiated ones and promoting their functional integration into the local neural circuitry. Studies thus far demonstrate that this approach may be – at least in theory – a practical and reasonable one. Thus far, the success of cell transplantation techniques has depended on the ability of transplanted cells to perform two global functions to replace, repair, and regenerate the damaged brain: namely neuroreplacement and neuroprotection (Madhavan and Collier 2010). One function of cell transplantation – neuroreplacement – hinges on the ability of exogenous NSPCs to replace damaged neural cells in a specific brain region. Neuroreplacement has been shown to be reasonably successful in circumstances where discrete, region-specific cell loss occurs before the appearance of, and as a cause of, neurological symptoms. For


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example, in animal models of PD, DA neural precursors derived from different animal species and cellular sources have been shown to survive, reinnervate the striatum, and mitigate motor symptoms when they are grafted in the substantia nigra or striatum (Yasuhara et al. 2006; Shim et al. 2007), two sites in the brain that are severely damaged and are responsible for the motor impairments observed in PD. Cell transplantation in this case has appeared to be relatively successful because massive loss of DA neurons occurs before motor symptoms develop and the neuron loss is also the cause of these symptoms. However, as described below, there has been mixed success in the long-term survival and integration of transplanted cells. In addition to replacing lost neurons, two recent studies report that NSPC transplantation may also stimulate neurogenesis in the aging hippocampus (Hattiangady et al. 2007; Park et al. 2010), reinforcing the view of exploiting the process of adult neurogenesis to enhance the neurogenic capacity of NSPCs, optimizing therapeutic results. Although the degree of neurogenesis in aged animals is lower as compared to younger animals, it falls in line with the proposed idea of fine-tuning the neurogenic capacity of adult NSPCs to enhance their ability to survive and incorporate into the aged brain.


A second function for transplanted NSPCs – often considered the primary mechanism underlying improvement or recovery following cell transplantation – is neuroprotection. This entails the ability of endogenous and/or grafted NSPCs to exert neuroprotective or ‘bystander effects’ to promote the survival of grafted neural cells and to prevent further tissue damage (Ourednik et al. 2002; Madhavan and Collier 2010). Neuroprotection emphasizes the importance of ‘niche’ effects on cell transplantation in which grafted NSPCs adapt their behavior and fate to the microenvironment to promote brain repair and regeneration (Ourednik et al. 2002; Riquelme et al. 2008; Madhavan and Collier 2010). This includes the interaction of endogenous and grafted NSPCs and their ability to secrete specific growth promoting factors and chemokines, including Notch receptor ligands, brain derived neurotrophic factor, nerve growth factor, and stromal derived factor-1 alpha (SDF-1α). An example of growth promoting molecules exerting neuroprotection in neurodegenerative diseases comes from a recent study demonstrating that the Notch receptor ligand, Delta-like 4 (DII4), induces Hes3 and sonic hedgehog (Shh) expression, thereby promoting NSPC survival and improving motor function in ischemic rats (AndroutsellisTheotokis et al. 2006). In a subsequent study using the 6-hydroxydopamine (6-OHDA) rat model of PD, the same group showed that NSPC activation by DII4 fosters the neuroprotection and recovery of injured DA neurons and restores motor function (Androutsellis-Theotokis et al. 2009). In addition to cell survival, secretion of growth and survival factors into the local niche allows grafted NSPCs to migrate to and survive in pathological sites. Upon arrival to the site of injury, transplanted cells survive in close proximity to the vasculature so they can interact with resident astrocytes and microglia and secrete additional growth factors vital for trophic support (De Feo et al. 2012). Transplantation-induced therapeutic effects via neuroprotection were elegantly documented in 2 recent studies examining DA neuroprotection in a rat model of PD (Yasuhara et al. 2006; Madhavan et al. 2012). These studies demonstrate that endogenous NSPCs could provide a suitable environment for transplanted NSPCs by modulating their survival,


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differentiation, growth factor expression, as well as their interaction with resident glia to stimulate neuroprotection of the injured nigrostriatal DA system.


Harnessing NSPCs for treatment of neurodegenerative disorders: current challenges and future strategies Clearly, progress has been made in using NSPCs for neuroreplacement and neuroprotection in humans (Bjorklund et al. 2003; Mendez et al. 2005; 2008). However, this approach is highly dependent on the characteristics of the damaged brain region, the specific cell type to be replaced, and the timing of transplantation relative to the time course of disease trajectory. In looking to future prospects on how to best implement the knowledge of NSPCs and neurogenesis to tackle neurodegenerative disorders, below we note several questions that are raised by current approaches. We also present strategies to answer these questions, relying heavily on the growing knowledge of regulatory mechanisms of adult neurogenesis, and incorporating new strategies that involve stimulation of endogenous NSPCs as well as utilization of exogenous NSPCs. What cell types are needed?


A major question that is raised by current approaches to using NSPCs to help in the fight against neurodegenerative disorders is what cell types should be replaced/introduced into the degenerating brain? This is not an easy question to answer. An excellent example of this conundrum is in PD. As reviewed above, PD is best known for the loss of DA neurons, but some studies suggest the loss of NE and 5HT neurons may be as much if not greater than the loss of DA neurons (Hedlund and Perlmann 2009; Kano et al. 2011; Politis et al. 2012). This is important, since DA-rich fetal grafts into the brains of patients with PD ameliorates motor dysfunction (Mendez et al. 2005; 2008), but may not mitigate non-motor symptoms that occur first and which may be caused by NE or 5HT neuron dysfunction (Aarsland et al. 2009; Delaville et al. 2011; Kano et al. 2011; Politis et al. 2012). Therefore, the widespread damage and loss of non-DA neurons that contributes to non-motor symptoms demonstrates the need to consider transplantation of cell types beyond DA cells (Politis et al. 2012). A similar concern exists in AD and HD; we need a better understanding of which neurons are lost, and which neuron loss is the main culprit in producing symptoms of the disorders.


In addition to neuron loss or dysfunction, non-neural cells such as astrocytes are also damaged in neurodegenerative diseases (Salminen et al. 2011). Glial cells have traditionally been viewed as support cells by providing metabolic support for neurons, regulating extracellular ionic and neurotransmitter content, and promoting angiogenesis, among other functions (Wang and Bordey 2008). However, we now know that glial cells – particularly astrocytes – play a more active role in regulating synapse formation and synaptic transmission, which are crucial for neural and cognitive function (Wang and Bordey 2008). Astrocytes also store and secrete many different trophic factors that can influence NSPC behavior and fate, which is essential for promoting neuroprotection in diseased regions of the brain (Wang and Bordey 2008). Neuroinflammation that involves glial cell activation has also been shown to occur in neurodegenerative diseases (Glass et al. 2010). Moreover, the NSPCs in the adult SGZ (Type-1 cells) and SVZ (B cells) have many glial-like


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characteristics (Song et al. 2002; Robel et al. 2011). The potential of glial-like cells to become neural stem cells and give rise to progenitor cells underscores that glial cells may be another source of new neurons. Intriguingly, it is possible neural stem cells could be encouraged to revert to astrocytes (Buffo et al. 2008; Robel et al. 2011), and thus provide many of the support functions that may help regulate homeostasis under conditions of neurodegeneration, such as buffering extracellular glutamate. In sum, once there is a better picture of the pathologies and the mechanisms underlying these disorders, basic scientists can then set about defining the parameters needed to coax cells – either endogenously or exogenously – into becoming a particular cell type. When to replace/repair?


Another related question is when should replacement or protection strategies be employed during the course of the disease? In some diseases, symptoms manifest well before cell loss, suggesting that effective strategies for neurodegenerative diseases may not be as straightforward as replacing cells that are lost. As mentioned above, patients with AD develop mild cognitive impairments long before evidence of synaptic and neuronal cell loss (Lazarov and Marr 2010). Only later – after cognitive symptoms become severe – is there a significant loss of brain volume and neurons in the hippocampus and cortex. This pathological timeline is also evident in a rat model of HD in which behavioral abnormalities precede the appearance of neuropathological markers (Nguyen et al. 2006). The temporal dissociation of onset between behavioral and pathological markers is indicative that the loss of neurons is an endpoint, and that other biological processes may contribute to the early neurological symptoms.


Obviously, if there is no overt cell loss during the early stages of AD when patients develop impaired cognition or in HD patients that develop motor dysfunction, then there is no rationale to replacing neurons at the early stage of disease. However, waiting until the disease progresses to the point of overt cell loss presents the additional challenge of transplanting cells into what may be an unfavorable environment. At later stages of disease, the affected area may be overcome with β-amyloid plaques, fibriliary tangles, and neuroinflammation, making it a highly inhospitable environment for the survival of transplanted cells. In the case of PD, there is already a near 80% loss of DA neurons in the SNpc by the time patients develop motor symptoms (Hedlund and Perlmann 2009). This sequence of events is in contrast to AD, and in the case of PD, cell replacement during the early stages may be a more desirable approach. Therefore, when exploiting NSPCs and neurogenesis to promote regeneration and brain repair, it is important to consider the timing of stem cell transplantation in relation to the timeline of disease trajectory. Importantly, this also emphasizes that neuroreplacement and neuroprotection strategies are best envisioned as dynamic, interrelated approaches to eventual treatment for these disorders. For example, perhaps early in disease progression, NSPCs are employed to provide neuroprotection and to maintain the “health” of the brain region, making it receptive to later attempts to transplant NSPCs or other cell types.


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Strategies to stimulate endogenous NSPCs?


The decline in neurogenesis levels along with the inhospitable environment in the aging and diseased brain can significantly diminish the neurogenic potential of NSPCs, making it a challenge to adequately replace neurons in sufficient numbers. Notably, there are advances in in vitro fate switching (Caiazzo et al. 2011; Kim et al. 2011; Yoo et al. 2011) and the use of induced pluripotent cells (iPSCs) (Selvaraj et al. 2010; Wu and Hochedlinger 2011). These research advances were built on the work for which John Gurdon (Gurdon 1962) and Shinya Yamanaka (Aoi et al. 2008) won the 2012 Nobel Prize in Medicine. Despite these enormous conceptual and technical advances, transplantation of NSPCs or related cells may not be practical for neurodegenerative disorders in the near future given our limited knowledge on the trajectory of the disorders (Table 1) and the limits of fate switching in regards to human treatment. Further complicating the matter, transplantation early in the disorders may carry more risks than benefits.


To address these limitations of utilization of transplanting exogenous NSPCs, one therapeutic strategy would be to augment endogenous neurogenesis in the dentate gyrus SGZ, the SVZ, or to even initiate neurogenesis in previously non-neurogenic regions. In this regard, one strategy is to recruit and expand NSPCs for differentiation into mature cell lineages. In regards to the hippocampus, Type-2 amplifying progenitor cells rapidly proliferate and make up the majority of the progenitor cell pool, making them a reasonable target for endogenous stimulation strategies. Increases in neurogenesis can be achieved physiologically, such as via voluntary exercise (van Praag 2009). Increases in neurogenesis can also be achieved pharmacologically, as has been shown via administration of compounds such as antidepressants (Petrik et al. 2012b). As both exercise and antidepressants ameliorate some of the symptoms of certain neurodegenerative disorders (Lazarov et al. 2010; Radak et al. 2010), it will be interesting to see whether these changes are linked to enhanced neurogenesis once human neurogenesis can be more reliably imaged in vivo (Sierra et al. 2011).


One exciting more recent development in pharmacologically-induced enhancement of endogenous neurogenesis is the implementation of small molecules (Schneider et al. 2008). Through the screening of high-throughput chemical libraries in stem cell-based assays, several small molecules have shown promise to enhance neurogenesis in laboratory animals (Schneider et al. 2008). This relatively new area of research into small molecule modulators of neurogenesis is ripe for exploration as a potential regenerative therapy. These small molecules have been found to enhance cognition by manipulating the phenotypic plasticity of cells at various stages of maturity. One group of such molecules is the 3,5-distrubted isoxazole compounds, which increase the number or differentiation of neurons (Schneider et al. 2008; Zhang et al. 2011). Specifically, isoxazole 9 (Isx-9) was recently revealed to promote hippocampal progenitor cell proliferation and neuroblast differentiation without depleting the neural stem cell pool and improves spatial memory in adult mice (Petrik et al. 2012a). Isx-9 also has therapeutic promise as it can induce terminally differentiated astrocytes to re-express neuronal genes and regain neurogenic potential in vitro (Zhang et al. 2011), revealing another way to recruit progenitor cells available for neuronal differentiation. Different small molecules also target different stages of neurogenesis; for


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example, KHS101 accelerates neuronal differentiation (Wurdak et al. 2010), and P7C3, prevents apoptosis of newborn neurons and improves cognition in aged rats (Pieper et al. 2010). Additional high throughput screening assays will likely lead to the discovery of additional neurogenic molecules and elucidate novel mechanisms regulating neurogenesis in healthy and pathological brain states. However, the identification of molecular targets and mechanisms of these neurogenic modulators remains to be clarified.


As hinted at in regards to the small molecule P7C3 above, stimulation of endogenous neurogenesis is not the only way to harness the regenerative power of NSPCs for neurodegenerative disorders; prevention of cell death may also be a way to maintain cell number or slow cell loss. In the normal brain, there appears to be a benefit of preventing cell death, as genetically-enhanced survival of hippocampal Type-2 cells enhances hippocampal function (Sahay et al. 2011; Dygalo et al. 2012). In the case of PD, overexpression of BclxL, an anti-apoptotic protein, enhanced survival of DAergic human NSPCs in vitro as well as in vivo (Liste et al. 2004). These studies demonstrate the utility of improving the “survival” of newborn neurons in order to improve neurological function (Martinez-Serrano et al. 2011). However, such concepts should be carefully employed in the context of neurodegeneration, since it is possible that more harm than good will result from forced survival of a cell that was previously destined for death.


There are other strategies to stimulate endogenous neurogenesis that are indicated in Figure 1. For example, one could target the “critical maturational period” of immature neuroblasts (Aasebo et al. 2011). Adult-born NSPCs that do not die during the first few days following cell birth possess distinctive physiological characteristics from mature granule cells while undergoing morphological maturation (Ge et al. 2007; Marin-Burgin et al. 2012). Immature neuroblasts possess higher membrane resistance, distinct firing properties, and lack glutamatergic input (Mongiat et al. 2009). These characteristics allow for a critical period of maturation in which immature granule cells can be influenced by various physiological and environmental stimuli. The hyperexcitability of immature neurons may be exploited in the context of neurodegenerative diseases. For example, if there are more immature neurons, they may serve to stimulate endogenous neurogenesis and contribute to behavior (Deng et al. 2009). One could also target the mature adult-generated neurons, for example by enhancing synaptic strength, integration into circuitry, or timing of maturation (Piatti et al. 2011). Both physiological and pharmacological approaches can be utilized to target these additional aspects of neurogenesis. In addition, as indicated in Figure 1, an exciting prospect for endogenous stimulation of neurogenesis to treat neurodegenerative disorders is to initiate cell migration to areas of the greatest need (Cayre et al. 2009). A number of studies have shown that NSPCs from the SGZ and SVZ are often redirected from their traditional migratory routes in the diseased brain (Fallon et al. 2000; Cooper and Isacson 2004; Tattersfield et al. 2004; Batista et al. 2006; Gordon et al. 2007; Winner et al. 2008a; Luzzati et al. 2011). Reorganization of cell migratory tracks would address the conundrum that endogenous neurogenesis is restricted to discrete brain areas, like the SVZ and SGZ, that are distinct from the brain areas where cells are lost in AD, PD, and HD. It is possible that future strategies targeting endogenous neurogenesis will facilitate migration of cells, for example, from the SVZ into the striatum Eur J Neurodegener Dis. Author manuscript; available in PMC 2015 February 25.

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to replace the medium spiny neurons lost in HD or supply DA in place of the DA terminals lost in PD (Cho et al. 2007; Arias-Carrion et al. 2009), or from the DG into the CA1 and cortex in AD. Indeed it has been shown that transplantation of exogenous NSPC in a rat model of PD triggers the expression of various trophic factors such as SDF-1α in endogenous NSPCs, leading to enhanced migration of endogenous NSPC to the graft site (Madhavan et al. 2009). Although the functional role of ectopic migration of NSPCs to diseased-affected regions remains to be clarified, there is extensive research investigating intrinsic and extracellular mechanisms of cell migration that could be used to stimulate NSPC migration to diseased-affected areas. These mechanisms include delivery of growth and survival factors and cytokines, extracellular matrix remodeling, vasculature remodeling, chemoattractive and chemorepulsive signaling, and regulation of DCX, PSA-NCAM, and other neurogenic molecules involved in chain migration (Cayre et al. 2009).

Conclusion


The term “neurodegeneration” has moved beyond referring simply to overt neuron loss. It now refers to complex and chronic disease processes in which numerous cell types are damaged and multiple biological processes are affected. As the view of neurodegeneration has evolved, our view of how to implement NSPCs and neurogenesis to fight AD, PD, and HD also has evolved. Researchers and clinicians are now thinking more broadly about how to harness the power of NSPCs and neurogenesis to ameliorate the neurological symptoms of each disease. Here we have stressed the importance of a better understanding of the pathological trajectory of each neurodegenerative disease. It is hoped that human brain imaging and post mortem studies will clarify the “needs” for each neurodegenerative disorder, including what cell types are needed? Neurons, astrocytes, or another cell type? Where are the cells needed? What factors might help the survival and integration of endogenous or exogenously implanted cells? We also encourage an approach where endogenous NSPCs of varying degrees of neural maturity in adult neurogenic regions can be fine-tuned so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. Ultimately, in order to achieve a more complete, long-term symptomatic relief, cell transplantation and endogenous stimulation therapies will need to be combined with other therapeutic approaches to alleviate all neurological symptoms.


Acknowledgments The authors thank Drs. Irene Masiulis and Sanghee Yun for helpful discussions and input in the preparation of this article. This work is supported by grants to AJE from the NIH (DA0167565, DA016765-07S1, DA023555) and NASA (NNX12AB55G). SEL is supported by a Diversity Fellowship (DA016765-09S1) from AJE’s NIH R01 grant.

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Figure 1.

Schematic depicting a sagittal view of a mouse brain with the 2 main adult neurogenic regions (top) and therapeutic strategies to promote the neurogenic capacity of endogenous NSPCs to augment physiological neurogenesis and restore neurological function (bottom). Top: Neurogenesis continues throughout adulthood in 2 main neurogenic regions: the SGZ of the hippocampal dentate gyrus (blue) and the SVZ along the lateral ventricles (orange). NSPCs generated in the SVZ migrate along the RMS (orange line) towards the OB and differentiate into interneurons in the olfactory bulb. Bottom: NSPCs of varying degrees of maturity can be targeted to increase the number of mature neurons available for functional incorporation into local neural networks. Possible therapeutic strategies can be targeted to Eur J Neurodegener Dis. Author manuscript; available in PMC 2015 February 25.

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induce neurogenesis in diseased regions by 1) stimulating NSPC differentiation into astrocytes; 2) stimulating the proliferation of rapidly dividing NSPCs; 3) promoting cell survival; 4) exploiting the hyperexcitability and critical maturational period of immature neurons; and 5) promoting cell maturation and synapse formation. It is also of therapeutic interest to promote NSPC migration to diseased-affected regions such as the SN or striatum in the case of PD and HD or to the cortex or area CA1 of the hippocampus in the case of AD (green dashed lines). This could be achieved via many cellular mechanisms originating from the local niche. Abbreviations: LV: lateral ventricle; DG: dentate gyrus; Ctx: cortex; Str: striatum; SN: substantia nigra; RMS: rostral migratory stream; SVZ: subventricular zone; SGZ: subgranular zone; OB: olfactory bulb.

NIH-PA Author Manuscript NIH-PA Author Manuscript Eur J Neurodegener Dis. Author manuscript; available in PMC 2015 February 25.

NIH-PA Author Manuscript Table 1



Eur J Neurodegener Dis. Author manuscript; available in PMC 2015 February 25. Autosomal dominant mutation due to expansion of CAG trinucleotide repeat in htt

Protein aggregation of mutant htt Loss of medium spiny GABA cells in SN Decreased GAD in Str and SN Decreased Ach in Str

• • •

5HT cell loss in DR

• •

Decreased DA levels in Str NE cell loss in LC

• •

Neuron and volume loss → Cognitive and motor dysfunction or Cognitive and motor dysfunction → Neuron and volume loss

Neuron and volume loss → Cognitive, mood dysfunction Motor dysfunction

Cognitive dysfunction → Neuronal and synaptic loss

Relative Pathological Trajectory (Cell Loss vs. Neurological Dysfunction)

Abbreviations: AD: Alzheimer’s disease; PD: Parkinson’s disease: HD: Huntington’s disease; APP: amyloid precursor protein; DA: dopamine; Str: striatum; SNpc: substantia nigra pars compacta; LC: locus coeruleus; DR: dorsal raphe; NE: norepinephrine; 5HT: 5-hydroxytryptamine (serotonin); htt: huntingtin gene; GABA: gamma aminobutyric acid; GAD: glutamic acid decarboxylase; Ach: acetylcholine.

•

HD

DA cell loss in SNpc

•

α-synuclein accumulation in Lewy bodies

•

Neurofibrillary tangles

•

Hyperphosphorylated Tau

Amyloid-β deposits in senile plaques

•

Soluble APP

•

Key Cytopathologies

•

Key Pathological Events

PD

AD

Disease

Simplified overview of the key neurological pathologies in Alzheimer’s, Parkinson’s, and Huntington’s diseases and the relative pathological trajectories of each disease in relation to the occurrence of cell loss and neurological dysfunction. Each neurodegenerative disease develops abnormal neurological features that eventually produce disease-specific pathologies and overt cell loss. Traditional cell replacement strategies aim to replace disease-affected neurons that are lost during disease progression. However, in some diseases, such as AD, it is thought that cognitive symptoms appear early in the disease trajectory before overt, gross loss of neurons, suggesting neuron replacement may not be effective (or may be too late). In the case of PD, patients may have substantial loss of multiple neuron types in many brain regions before they are officially diagnosed with the disease, suggesting neuron replacement strategies have to be equally diverse and complex. In the case of HD, it is still unclear whether neurological dysfunction manifest before significant neuron loss or vice versa. These examples illustrate the need to engineer NSPCs of varying degrees of neural maturity to address disease-specific pathologies at specific time points during the trajectory of disease, and underscore the need for improved clarity on the pathology and pathological timelines of these disorders.

Simplified timeline trajectories for key neurological pathologies in AD, PD, and HD in relation to cell loss and neurological dysfunction

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