Mammalian Subventricular Zones: Their Roles in Brain Development, Cell Replacement, and Disease

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Furthermore, induced pluripotent stem cells are a potential autologous source of replacement cells since they can be generated from a patient's own cells. Recent reports indicate that dopaminergic neurons derived from induced pluripotent stem cells can survive and provide functional improvement in rodent PD model systems Wernig et al.

Rutgers New Jersey Medical School

Advancing induced pluripotent stem cells to a clinical setting faces many of same challenges confronting the use of embyronic stem cells, including improvement in the dopaminergic neuron yields and prevention of tumor formation in the recipient. Neural stem cells are an alternative source of replacement neurons. These cells lack the pluripotent potential of embryonic and induced pluripotent stem cells, but they also do not have the same teratoma or tumor forming potential.

Fetal tissue is a rich source of neural stem cells that can generate a wide array of neuronal phenotypes, but as discussed above, the use of fetal tissue is fraught with moral and ethical problems. By contrast, adult neural stem cells do not have these issues, although they typically generate a more limited number of neuronal phenotypes.

In the adult mammalian brain, there are two well-established neurogenic niches: Neurons generated in both of these regions are able to integrate into pre-existing neural circuitry, which makes them attractive candidates for cell replacement therapy. Progenitors generated in the subgranular zone migrate to the dentate gyrus and become excitatory glutamatergic granule cells. Subgranular zone neural stem cells are located within the interior of the hippocampus, however, and extracting them without damaging the hippocampus is difficult.

SVZ neural stem cells almost exclusively produce inhibitory GABAergic inhibitory interneuron progenitors that migrate to the olfactory bulb glomerular and granule cells layers production of a small number of excitatory neurons has also been reported in Brill et al. SVZ neural stem cells reside within the walls of the lateral ventricle and, by penetrating non-eloquent parts of the brain in humans, they can be endoscopically harvested, expanded in vitro and differentiated into both neuronal and glial progenitors Westerlund et al.

Thus, adult SVZ neural stem cells are a potential clinically feasible source of autologous replacement neurons. Similar to other sources of donor cells, the survival rates of transplanted SVZ cells were consistently low. Also similar to clinical trials with fetal tissue, migration of transplanted SVZ cells away from the injection site was greater with dispersed SVZ cultures or neurospheres than with engraftments of tissue explants.

Mammalian Subventricular Zones: Their Roles in Brain Development, Cell Replacement, and Disease

Summary of studies transplanting adult SVZ-derived cells into the adult striatum. An unexpected and consistent finding in the rodent studies with SVZ-derived cells was the meager differentiation and survival of transplanted neurons. Using either cell suspensions or tissue explants as donor material, many of the surviving cells displayed glial phenotypes and very few expressed markers of mature neurons. The poor neuron yields were surprising since the adult SVZ normally produces large numbers of neuronal progenitors Luskin, ; Lois and Alvarez-Buylla, Analyses of SVZ progenitor cultures expanded in vitro found a large percentage of cells expressed glial marker genes prior to transplantation Richardson et al.

A majority of cells that survived a month after transplantation were found to have a mature a neuronal phenotype and only a few cells expressed the glial marker GFAP. The reasons for higher levels of neuronal generation and survival in this study are unclear. The interactions between adult SVZ neural stem cells and their surrounding niche are complex and only just becoming understood reviewed in Ihrie and Alvarez-Buylla, Despite their poor neuronal differentiation and survival, transplants of SVZ-derived cells into the host striatum did provide some functional recovery in 6-hydroxydopamine lesioned rodent PD models a month after surgery Meissner et al.

The extent of the improvement was variable, but it does suggest that introduction of glia is not deleterious and may produce some short-term symptomatic improvement. In addition to the poor differentiation and survival of neurons with SVZ-cell transplants, few, if any, of the detectable neurons displayed dopaminergic features. The human clinical trials clearly showed that integration and survival of dopaminergic neurons is essential for sustained long-term functional improvement.

Embryonic and induced pluripotent stem cells can be directed toward a dopaminergic cell fate by culturing them with appropriate growth factors and morphogens Kriks and Studer, ; Boyer et al. Similar protocols can significantly improve neuronal progenitor yields in cultured SVZ cells, but they do not direct these cells to a dopaminergic cell fate Deleidi et al. These protocols can generate dopaminergic neurons, however, if the SVZ progenitors are first converted into pluripotent stem cells by Oct4 over-expression Deleidi et al.

Oct4 has a central role in stem cell pluripotency and differentiation, and is sufficient to reprogram adult neural stem cells into pluripotent stem cells Pesce and Scholer, ; Kim et al. Transplantation of cultures with these reprogrammed dopaminergic neurons into 6-hydroxydopamine lesioned rats produced significant and reproducible functional improvement for up to 2 months after the procedure Deleidi et al.

An alternative genetic engineering strategy for improving dopaminergic neuron yields is to over-express transcription factors that specify cell fate during normal development. This approach has been successfully used with both embryonic and induced pluripotent stem cells Chung et al. Both Mash-1 and Nurr1 genes encode transcription factors that are involved in the specification of midbrain dopaminergic neurons Park et al. Transplantation of these cells in 6-hydroxydopamine lesioned rats also produces robust functional improvement. Adult SVZ neural stem cells normally generate dopaminergic interneurons and both Mash1 and Nurr1 -family transcription factors are important for specification of these interneurons Cave and Baker, Although the over-expression of Mash1 and Nurr1 was intended to generate dopaminergic neurons with a midbrain phenotype, this strategy may have generated either A16 olfactory bulb dopaminergic neurons or hybrid A16 neurons.

The ability of the dopaminergic neurons generated by Shim and co-workers to significantly improve functional performance in the rodent PD model, raises the possibility that either an A16 or a hybrid A16 dopaminergic neuron is a viable alternative for cell replacement strategies. Non-midbrain dopaminergic neurons are not typically considered for replacement cells in PD.

This is due, in part, to studies of transplanted dopaminergic neurons from non-mesencepahlic brain regions.

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Grafts of diencephalic dopaminergic neurons from either rodent or human embryonic hypothalamic tissue poorly integrated into the host striatum and provided no significant functional benefit in PD models Abrous et al. Furthermore, previous clinical trials grafting tissue containing catecholaminergic neurons from non-brain regions, including the adrenal medulla, carotid body, retinal epithelium and sympathetic ganglion neurons, demonstrated either only marginal or no significant benefit.

In addition, morbidities associated some procedures, such as autografts of either adrenal medulla and sympathetic ganglia, have further discouraged exploration of non-midbrain phenotypes as replacement cells reviewed in Wijeyekoon and Barker, Olfactory bulb dopaminergic neurons have several favorable attributes, however, that are distinct from these previously tested non-midbrain phenotypes.

Like other adult-generated neurons, olfactory bulb dopaminergic progenitors can integrate into pre-existing neural circuitry. Like their counterparts in the substantia nigra, a prominent electrophysiological property of olfactory bulb dopaminergic neurons is a capacity to generate auto-rhythmic action potentials Pignatelli et al.

Unlike the substantia nigra, however, olfactory bulb dopaminergic neurons are not vulnerable in PD-mediated neurodegeneration Huisman et al. Whether this accumulation adversely affects the function or survival of replacement neurons is not known, but it does suggest that replacement neurons of the midbrain phenotype are susceptible to PD in the long-term. Replacement neurons with the olfactory bulb dopaminergic phenotype, however, are expected to be less vulnerable to this pathology. Developing adult SVZ cells into a clinically suitable autologous source of replacement neurons faces several challenges.

One challenge is to enhance survival rates of engrafted cells. Studies with embryonic and induced pluripotent stem cells, for which long-term survival is also an issue, have indicated that treating the donor cells with antioxidants or growth factors can increase survival rates Nakao et al. The presence of neurotransmitters in the culture conditions may improve the ability to expand and differentiate cells with neuronal phenotypes since neurotransmitters can modulate proliferation, migration and survival of SVZ-derived cells in the endogenous SVZ neurogenic niche reviewed in Young et al.

In addition, pre-conditioning recipients by administering growth factors may also be an important strategy to improve long-term survival Chen et al. Elucidating culture conditions that promote neuronal progenitor expansion and survival will be critical for developing standardized preparations to generate clinically suitable replacement cells from adult SVZ neural stem cells. A second challenge is the suppression of glial progenitor proliferation and survival. SVZ neural stem cells prodigiously generate neuronal progenitors in their endogenous niche, but most of the progenitors generated by these cells either do not to survive or they adopt alternative fates when cultured in vitro and transplanted into the striatum.

Furthermore, proportional levels of glial production increase with either the age of the SVZ neural stem cell donor or the length of time that the stem cells are cultured Gritti et al. Since most PD patients are advanced in age, the propensity of autologously derived SVZ stem cells to produce glia is an important challenge to address. Protocols for in vitro expansion of SVZ progenitors typically use growth factor combinations that include epidermal growth factor EGF Deleyrolle and Reynolds, The inclusion of this growth factor, however, may be detrimental for neuronal progenitor production since stimulation of EGF receptors promotes glial progenitor proliferation and differentiation in the SVZ Aguirre and Gallo, ; Gonzalez-Perez and Quinones-Hinojosa, ; Gonzalez-Perez and Alvarez-Buylla, Alternatively, culture media may require other growth factors to suppress glial differentiation.

Expansion of neurospheres derived from the adult SVZ in media containing both EGF and FGF9 enhances neuronal proliferation while diminishing both oligodendrocyte and astrocyte progenitor production Lum et al. Supplementing in vitro culture conditions with Noggin may also enhance suppression of glial phenotypes.

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SVZ neural stem cells and neural progenitors express BMP receptors and antagonism of these receptors by Noggin inhibits glial differentiation Lim et al. Furthermore, cell-sorting techniques can facilitate the removal of glial progenitors from SVZ-derived cultures prior to transplantation. Recent studies with human pluripotent progenitors showed that glial progenitors can be successfully isolated from mixed cultures based on co-expression of CD44 and CD Yuan et al. A third challenge is developing efficient methods to produce dopaminergic neurons.

Treatment either with growth factors, morphogens, signaling molecules, or chromatin modifying agents does not direct SVZ-derived progenitors toward a dopaminergic fate. By contrast, significant dopaminergic neuron production has been only achieved through genetic modification of SVZ-derived progenitors Shim et al.

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  4. These genetic engineering methods, however, come with some caveats. Reprogramming of SVZ neural stem cells into pluripotent cells prior to dopaminergic differentiation introduces the same safety concerns associated with induced pluripotent stem cell strategies. Retroviral transduction of SVZ progenitors to over-express transcription factor genes, such as Nurr1 and Mash1 , avoids the concerns of genetic reprogramming, but retroviruses are questionable for clinical application since they can increase the risk of tumor formation by disrupting endogenous gene expression upon their insertion into the host genome Yi et al.

    Genetically engineering SVZ progenitors for cell replacement therapy in PD will likely require one of the other available methods to transduce cells Lowry and Plath, Even though over-expression of Nurr1 and Mash1 has provided the best yield of SVZ-derived dopaminergic neurons to date, only a subset of transduced cells adopted a dopaminergic phenotype.

    This partial induction may reflect the heterogeneity within the SVZ stem cell niche. Specific subsets of olfactory bulb interneurons are generated from the neural stem cells that are spatially localized in distinct regions of the adult SVZ Kelsch et al. Further studies are required to establish whether adult SVZ neural stem cells from spatially distinct regions are limited in their capacity to generate dopaminergic progenitors in vitro.

    In addition to transcription factors, heterogeneous expression of microRNAs may also be instrumental in shaping the in vitro potential of adult SVZ neural stem cells to generate dopaminergic neurons De Chevigny et al. Further studies are also required to address whether the dopaminergic neurons produced with SVZ-derived progenitors either adopt an olfactory bulb, midbrain or a hybrid dopaminergic phenotype. As discussed above, the olfactory bulb phenotype may be clinically advantageous for replacement cells, but one concern is that olfactory bulb dopaminergic interneurons also co-express of GABA Kiyokage et al.

    The effect of GABA in these potential replacement cells is difficult to predict, but recent studies suggest that nigral dopaminergic neurons inhibit striatal output through the co-release of both dopamine and GABA Tritsch et al. Thus, the co-expressed GABAergic phenotype in olfactory bulb dopaminergic interneurons may be more of a similarity than a difference with nigral dopaminergic neurons. Studies in rodent PD animal models are needed, however, to demonstrate whether the olfactory bulb or a hybrid dopaminergic phenotype can provide functional recovery without producing deleterious side effects.

    The adult SVZ is a promising source of neural stem cells to generate dopaminergic neuronal progenitors for cell transplant strategies in PD. Since these stem cells can be endogenously harvested from patients, they are a potential autologous source of replacement cells. As discussed in this review, however, there are several important technical issues to be addressed in order for adult SVZ neural stem cells to be competitive source for clinically suitable dopaminergic neurons.

    The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Neurosci v. Published online Feb This article was submitted to Neurogenesis, a section of the journal Frontiers in Neuroscience.

    Received Nov 29; Accepted Jan The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    Orly Lazarov - Neurogenesis, cognitive dysfunction and Alzheimer's disease

    This article has been cited by other articles in PMC. Abstract Clinical trials engrafting human fetal ventral mesencephalic tissue have demonstrated, in principle, that cell replacement therapy provides substantial long-lasting improvement of motor impairments generated by Parkinson's Disease PD. Ideal features of replacement cell sources Analyses of the clinical trials identified several features of replacement cells that are essential for favorable functional outcomes Wijeyekoon and Barker, ; Lindvall and Bjorklund, Embryonic and induced pluripotent stem cell sources The ideal source of replacement cells for PD has not been established reviewed in Meyer et al.

    Replacement cells derived from the adult SVZ Adult neural stem cells Neural stem cells are an alternative source of replacement neurons. Table 1 Summary of studies transplanting adult SVZ-derived cells into the adult striatum. Open in a separate window. Dopaminergic differentiation of SVZ progenitors In addition to the poor differentiation and survival of neurons with SVZ-cell transplants, few, if any, of the detectable neurons displayed dopaminergic features.

    Challenges for developing adult SVZ cells as replacement cells Developing adult SVZ cells into a clinically suitable autologous source of replacement neurons faces several challenges. Conclusions The adult SVZ is a promising source of neural stem cells to generate dopaminergic neuronal progenitors for cell transplant strategies in PD.

    Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Development of intracerebral dopaminergic grafts: Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination.

    Identification of intrinsic determinants of midbrain dopamine neurons. Cell , — Glial cell line-derived neurotrophic factor improves intrastriatal graft survival of stored dopaminergic cells. Neuroscience 83 , — Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Dopaminergic differentiation of human pluripotent cells. Stages in the development of Parkinson's disease-related pathology.

    Adult generation of glutamatergic olfactory bulb interneurons. Graft placement and uneven pattern of reinnervation in the striatum is important for development of graft-induced dyskinesia. Dopamine systems in the forebrain. Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology.

    Roles of the mammalian subventricular zone in brain development.

    Creating a neurogenic environment: Neural progenitor cells derived from the adult rat subventricular zone: Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells. The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons.

    Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons. Long-term outcome of unilaterally transplanted parkinsonian patients. Brain Pt 1 , 41—50 Oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neurons. The control animals treated with l -DOPA showed no significant difference in proliferation. To ensure that l -DOPA was converted to dopamine in lesioned animals, we examined the concentration of dopamine in the striatum of lesioned animals treated with l -DOPA compared with untreated lesioned animals by HPLC.

    The dopaminergic nigrostriatal tract was lesioned by 6-OHDA. NPCs born in the SVZ migrate out along the rostral migratory stream where they differentiate into neurons in the olfactory bulb OB 2 , 16 , Non-neuronal precursors generate glia and migrate to the striatum, corpus callosum, or neocortex after injury To determine whether the neuronal fate of the newly-generated precursors was affected as a result of alterations in dopamine and EGF levels, lesioned animals with or without l -DOPA and control animals were examined for levels of proliferation and newborn neuronal differentiation in the OB 21 days after the last BrdU injection.

    The subjects studied were 75—83 years of age, had a mini mental state examination MMSE score ranging from 12 to 21, had advanced PD Hoehn and Yahr stage 3—5 , and were taking a combination of l -dopa medications. At this stage of disease there is extensive dopaminergic denervation of the striatum and the ability to convert l -dopa to dopamine is compromised, accounting for the on—off phenomena that characterizes this stage of disease. As a result, the ability of the synthesized dopamine to release EGF in these patients would be significantly affected and this coupled with the absence of medication being taken in the agonal stages of the illness would account for the down-regulation of EGFR seen in these patients at postmortem.

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    It would be very interesting to know whether PD patients in the early stages of the disease have similar abnormalities in the face of a more functionally-intact dopaminergic nigrostriatal pathway. The present study has provided extensive evidence for a role for EGF as a key mediator of dopamine-induced neurogenesis in the adult SVZ, which in turn may have implications for PD. In addition, we, and others have shown that dopaminergic receptor activation controls the proliferation of adult NPCs in vitro 9 , 19 , 20 , suggesting that dopamine might interact with the EGFR in this neurogenic niche to promote proliferation.

    However, this is unlikely to be the only pathway, and indeed D2 receptor activation has recently been shown to promote neurogenesis through the regulation of ciliary neurotrophic factor expression in the SVZ This result identifies dopamine as an endogenous regulator of EGF expression in the SVZ, which may be of crucial significance in diseases with impaired dopaminergic signaling.

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    Dopamine receptors are G protein-coupled receptors GPCRs , and it is now well described that GPCR-induced transactivation of EGFR 22 , 23 , as would be the case for dopamine stimulation, regulates cellular functions such as proliferation. However, the exact PKC isoform mediating this has yet to be identified. C cells divide rapidly in vivo, and activation of the EGFR has been identified as the regulator of controlled C-cell amplification.

    This result can easily be explained with reference to a previous study 8. Second, C cells correspond to the EGF-responsive cell in vivo but behave as multipotent B cells in vitro when exposed to EGF, possibly because of the absence of the glial microenvironmental signals 4 , 8. In vivo studies then confirmed that dopamine denervation significantly reduced NPC proliferation in the adult SVZ as reported 9 , However, of greater interest is the finding that local EGF release is significantly reduced in the SVZ of dopamine-denervated animals.

    This may be because the intact system is already maximally activated with respect to this EGF pathway, an observation that may help explain why the SVZ NPCs are relatively insensitive to environmental manipulation in contrast to the NPCs of the dentate gyrus. This increase in OB neuronal differentiation is different from that reported with exogenous EGF administration, in which there was a change in the astrocytic, not neuronal, fate of NPCs in vivo 5.

    These conflicting results may be explained by the fact that chronic high concentrations of exogenous EGF were used in these studies, doses that led to the induction of pronounced hyperplasias in the ventricular wall, whereas the EGF released as a consequence of dopamine stimulation is endogenous and at more physiological concentrations. Moreover, prolonged exposure to high doses of EGF has been shown to arrest neuroblast production and promote the genesis of highly-proliferative glia-like cells 8.

    The contribution of neurogenesis to the pathology of neurodegenerative disorders is an area of intense interest. Neurogenesis has been shown to be altered in a number of neurodegenerative diseases including Alzheimer's disease 24 — 26 , Huntington's disease 27 , 28 , ischaemic and traumatic brain injury 29 , 30 , and PD 10 , Odor memorization has been impaired in experimental animals with reduced neurogenesis 32 , which is of considerable interest in PD as the identification and discrimination of odors is impaired in a large proportion of PD patients It is possible that this process may lead to olfactory dysfunction in PD.

    All of this work has been done in either rodent cultures or rat models of PD, and its relevance to the human brain and PD is unknown. This result is consistent with our experimental data and would support an interaction between dopamine and EGFR in human PD and could suggest that the pathway identified in rodents is conserved across all mammalian species, including humans. In summary, the process of neurogenesis in the SVZ involves the orchestration of 4 distinct events to yield functional newborn neurons: In the absence of dopamine, the first step in the process of neurogenesis proliferation is negatively affected such that the size of the proliferative pool in the SVZ is significantly reduced, and as a consequence the downstream events will also be affected in a similar way.

    This, in turn, may have implications for the treatment and pathogenesis of dopaminergic disorders of the CNS such as PD. Experiments were carried out according to the U. Female Sprague—Dawley rats — g , received unilateral medial forebrain bundle injections of 6-OHDA as described Two weeks later, rats were challenged with d -amphetamine 2. Adult rodents were killed by CO 2 asphyxiation, and the SVZ was dissected, diced with a scalpel blade, and digested with trypsin 0. Digestion was stopped by 0. Cells were grown in neurosphere medium: Primary neurospheres were passaged to produce secondary neurospheres on day For proliferation and differentiation experiments, primary neurospheres were dissociated and grown in neurosphere medium.

    On day 3, cultures were pulsed with 0. These were visualized by using biotinylated secondary antibodies 1: For antibodies used see Table S2. Primary neurospheres were dissociated and grown in neurosphere medium. The absorbance of the formazan product was determined at a wavelength of nm by using a plate reader. NSC numbers were analyzed as described 37 , The next day, the plate containing 1 cell per well was examined and only wells with 1 cell per well were analyzed further.

    After 7 days, the number of neurospheres per well was counted and plotted against the number of cells plated per well. In addition, the number of wells in the 1 sphere per well plates that contained neurospheres was counted and expressed as a percentage of cells plated. Cells were dissociated and fixed on ice. Cell cycle analysis was carried out with a Moflo Flow cytometer Dakocytomation. The percentage of cells in different stages of the cell cycle was determined with Summit 4. Cells were prepared as for cell cycle analysis. Each experiment was performed in triplicate, and the intensity of the EGF bands was quantified densitometrically and normalized to the corresponding actin control.

    Counting was performed blind to treatment condition. Absolute values for cell counts in the SVZ of each brain were calculated by multiplying the ratio of reference volume to sampling volume. For quantitative analysis of in vitro experiments, images were taken with a Leica DM fluorescence microscope, FX camera, and FW software. All experiments were carried out a minimum of 3 times from independently-generated cultures for in vitro work and 6 times for in vivo experiments, unless otherwise stated. This work was supported by a Medical Research Council studentship to G.

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    Barker , and Maeve A. PNAS May 26, 21 ; https: Abstract A reduction in dopaminergic innervation of the subventricular zone SVZ is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease PD. Discussion The present study has provided extensive evidence for a role for EGF as a key mediator of dopamine-induced neurogenesis in the adult SVZ, which in turn may have implications for PD.

    Footnotes 2 To whom correspondence should be addressed. The authors declare no conflict of interest. A longitudinal investigation of the kinetics, migration, and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions. J Comp Neurol Doetsch F , Garcia-Verdugo JM , Alvarez-Buylla A Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. Morshead CM , et al. A relatively quiescent subpopulation of subependymal cells.

    Craig CG , et al.