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  1. 1. Journal of Molecular Cell Biology Advance Access published May 10, 2012doi:10.1093/jmcb/mjs016 Journal of Molecular Cell Biology (2012), Vol no. 0, 1 – 7 | 1ReviewRegenerative medicine using adult neural stemcells: the potential for diabetes therapyand other pharmaceutical applicationsTomoko Kuwabara and Makoto Asashima*Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Central 4, 1-1-4 Higashi, Tsukuba Science City305-8562, Japan* Correspondence to: Makoto Asashima, E-mail: m-asashima@aist.go.jpNeural stem cells (NSCs), which are responsible for continuous neurogenesis during the adult stage, are present in human adults.The typical neurogenic regions are the hippocampus and the subventricular zone; recent studies have revealed that NSCs also existin the olfactory bulb. Olfactory bulb-derived neural stem cells (OB NSCs) have the potential to be used in therapeutic applicationsand can be easily harvested without harm to the patient. Through the combined influence of extrinsic cues and innate programming,adult neurogenesis is a finely regulated process occurring in a specialized cellular environment, a niche. Understanding the regu-latory mechanisms of adult NSCs and their cellular niche is not only important to understand the physiological roles of neurogenesisin adulthood, but also to provide the knowledge necessary for developing new therapeutic applications using adult NSCs in otherorgans with similar regulatory environments. Diabetes is a devastating disease affecting more than 200 million people worldwide.Numerous diabetic patients suffer increased symptom severity after the onset, involving complications such as retinopathy andnephropathy. Therefore, the development of treatments for fundamental diabetes is important. The utilization of autologous cellsfrom patients with diabetes may address challenges regarding the compatibility of donor tissues as well as provide the meansto naturally and safely restore function, reducing future risks while also providing a long-term cure. Here, we review recent findingsregarding the use of adult OB NSCs as a potential diabetes cure, and discuss the potential of OB NSC-based pharmaceutical applica-tions for neuronal diseases and mental disorders.Keywords: neural stem cells, olfactory bulb, diabetes, insulin, modeling pathogenesis, pancreasIntroduction (GFAP), and the Sry-related high-mobility group (HMG)-box tran- Neural stem cells (NSCs) are defined as undifferentiated cells scription factor Sox2 (Fukuda et al., 2003, Garcia et al., 2004).that can self-renew as well as give rise to the differentiated cell The cells have a radial process spanning the entire granule celllines that constitute the central nervous system (CNS): neurons, layer, and ramify into the inner molecular layer. Sox2-positiveastrocytes, and oligodendrocytes (Gage et al., 1995; Gage, 2000; type 2 NSCs have only short processes and do not expressOkano, 2002; Ma et al., 2010; Figure 1). Neurons are the functional GFAP. These type 2 NSCs, present in the dentate gyrus regioncomponents of the CNS and are responsible for information pro- of the hippocampus, can self-renew, and a single Sox2-positivecessing and transmission; astrocytes and oligodendrocytes are NSC can give rise to a neuron or an astrocyte in vivo (Suhknown as ‘glia’ and play supporting roles that are essential for et al., 2007). The transcription factor Sox2 is important for main-the proper neuronal function (Abematsu et al., 2006; Basak and taining the ‘multipotency’ not only of adult NSCs but also of em-Taylor, 2009). Active adult neurogenesis is restricted, under physio- bryonic stem cells (ESCs; Zappone et al., 2000; D’Amour andlogical conditions, to two specific ‘neurogenic’ brain regions, the Gage, 2003; Ferri et al., 2004).subgranular zone (SGZ) in the dentate gyrus of the hippocampusand the subventricular zone of the lateral ventricles (Gage, 2000; Adult NSCs retaining multipotency express Sox2Kempermann and Gage, 2000). The sources of the neurogenic Stem cells, or undifferentiated cells, in vertebrates (Asashimaadult NSCs are present in these regions. et al., 1990, 2008, 2009; Okabayashi and Asashima, 2003; The two types of progenitor cells are present in the SGZ and are Kurisaki et al., 2010) are broadly classified into two types:distinguished by their distinct morphologies in the hippocampus. ESCs, which are present during the embryonic stage, and adultType 1 progenitor cells express nestin, glial fibrillary acidic protein stem cells, which are present in the tissues of adults. The HMG-box transcription factor Sox2 is expressed in ESCs and in# The Author (2012). Published by Oxford University Press on behalf of Journal of the most uncommitted cells in the developing CNS (NishimotoMolecular Cell Biology, IBCB, SIBS, CAS. All rights reserved. et al., 1999; Ferri et al., 2004). The expression of the Sox2
  2. 2. 2 | Journal of Molecular Cell Biology Kuwabara and Asashima undifferentiated state in vitro. NSCs are isolated and cultured in the presence of a defined concentration of the basic fibroblast growth factor (FGF) and/or epidermal growth factor (EGF) under serum-free conditions (Johe et al., 1996). Insulin-like growth factor-1 (IGF-1) and IGF-2 are secreted proteins that have been demonstrated to promote neuronal survival by preventing their natural cell death (De Pablo and de la Rosa, 1995). IGF-1 is also required for an FGF-2-mediated promotion on the proliferation and survival of neurons in vitro (Drago et al., 1991). As mentioned previously, multipotent NSCs can be derived from the olfactory bulb (Pagano et al., 2000; Dictus et al., 2007; Kuwabara et al., 2011), and FGF-2 is required to maintain the NSCs in an undifferen- tiated and proliferative state. The maintenance of their undifferen- tiated state is mediated by the promotion of the expression of genes such as Sox2. As may be inferred from this description, the main-Figure 1 Schematic representation of the signals and transcription tenance of multipotent stem cells in vitro requires complex regula-factors regulating adult neurogenesis. Adult NSCs express the Sox2 tran- tion by a number of signaling mechanisms (Figure 1).scription factor to maintain the undifferentiated state. FGF-2 promotesthe self-renewal of NSCs and IGF-1/2 supports the process. Astrocyte-secreted Wnt3 promotes the neuronal differentiation from NSCs by Insulin and neurogenesisthe activation of the NeuroD1 transcription factor in the neuronal pro- Insulin appears to have a necessary role in brain functiongenitor cell. The NeuroD1 transcription factor triggers the expression (Wickelgren, 1998), including the hippocampal energy metabol-of the insulin gene. Insulin and IGF-1/2 promote the oligodendrocyte dif- ism (Hoyer et al., 1996) and the facilitation of learning andferentiation from NSCs and also enhance the survival of neurons. memory (Craft et al., 1996). Energy metabolism is an essential regulator of the function of adult NSCs (Rafalski and Brunet,transcription factor helps to maintain stem cell populations in a 2010). Among the various signaling molecules, insulin, IGF-1,multipotent state during embryonic development, and its ablation and IGF-2 provide instructive signals for regulating the fate ofcauses early embryonic lethality (Avilion et al., 2003). An enforced adult NSCs (Hsieh et al., 2004; Figure 1). Insulin and IGF-1 recep-expression of four transcription factors (Oct4, Klf4, c-Myc, and Sox2) tors are widely expressed in the brain (Aberg et al., 2003; Hsiehin differentiated somatic cells can induce them to adopt a phenotype et al., 2004), and insulin and IGFs have been demonstrated tosimilar to ESCs (induced pluripotent stem cells, iPSCs) (Takahashi have mitogenic effects on NSCs (Arsenijevic et al., 2001). IGF-1and Yamanaka, 2006; Baker, 2007). Since human iPSCs share can stimulate neurogenesis in the dentate gyrus (Aberg et al.,many characteristics with human ESCs, reprogrammed iPSCs offer 2000), as well as increase the proliferation and neuronal differen-opportunities for the creation of autologous cellular therapies tiation of EGF-responsive multipotent NSCs derived from E14(Gekas and Graf, 2010; Weir et al., 2011; Maury et al., 2012). mouse striatum (Arsenijevic et al., 2001). The overexpression of Sox2 is expressed by endogenous NSCs and by the vast majority IGF-1 in transgenic mice results in an increased brain size andof dividing precursors in the neurogenic regions of the adult brain myelin content (Carson et al., 1993). Conversely, IGF-1 knockoutto maintain their proliferation. Ferri et al. (2004) showed that Sox2 mice have smaller brains and CNS hypomyelination (Carson et al.,is expressed in proliferating precursor cells in vivo and in adult 1993; Beck et al., 1995).brain-derived NSC cultures in vitro. Similarly, a Sox2 deficiency It is well known that diabetes impairs hippocampal learningwas shown to cause neurodegeneration and impaired neurogen- and memory (Stranahan et al., 2008). Diabetes mellitusesis in adults. In the hippocampus, Sox2-expressing NSCs were (Terauchi and Kadowaki, 2002; Kadowaki et al., 2003;shown to give rise to neurons and glia as well as NSCs that Kadowaki, 2011; Naito et al., 2011) is associated with moderateretain Sox2 expression (self-renewal). This was demonstrated at impairments in cognitive function and patients present a highthe single-cell level by using the lentivirus- and retrovirus-mediated risk of affective disorders, dementia, and Alzheimer’s diseasefate-tracing studies (Suh et al., 2007). (Ott et al., 1999; Brismar et al., 2007). The pathogenesis of The olfactory bulb, the part of the brain that receives the axonal these deficits is multifactorial, probably involving other micro-input from the sensory neurons in the nose, also contains NSCs. vascular dysfunction and oxidative stress, and the mechanismThe identification and isolation of NSCs from the adult human has not been fully elucidated. Independent studies, using dia-brain has been seen as an exciting discovery, raising hopes for betes animal models, indicated that diabetes is associated withtheir use in the treatment of neurodegenerative diseases. reduced neural progenitor proliferation and neurogenesisNeurogenesis in the olfactory bulb is tightly regulated such that (Stranahan et al., 2008; Guo et al., 2010). The inability tothe number of mature sensory neurons is maintained at a con- produce insulin at efficient levels causes detrimental effects onstant surface density (Mackay-Sim et al., 1988; Kuhn et al., adult neurogenesis and synaptic neuronal plasticity (Stranahan2005). The signals that support populations of proliferating et al., 2008). Unregulated glucose levels (hyperglycemia) are det-stem cells, or precursor cells, influence the final numbers of rimental to the neurogenesis originating from adult NSCs, which,neurons derived from these populations. Similarly, a variety of in turn, may play a role in the cognitive decline observed insignaling proteins are required to maintain NSCs in their humans with diabetes (Craft and Christen, 2010).
  3. 3. Regenerative medicine using adult neural stem cells Journal of Molecular Cell Biology | 3Insulin expression in neurons neurogenesis (Song et al., 2002; Okamoto et al., 2011). In Drosophila, insulin is produced by neurons within the brain As people age, the number of adult NSCs decreases significantly,(Brogiolo et al., 2001; Rulifson et al., 2002). Clusters of these as does their ability to generate diverse neuronal populationsinsulin-producing cells in the brains of flies and the vertebrate (Lee et al., 2011). The frequency of neurogenesis varies signifi-pancreatic islet b cells are considered the functional analogs cantly with the environment in which an individual lives, withthat evolved from a common ancestral insulin-producing neuron stress and disease having a negative impact on the process. In(Rulifson et al., 2002). There are considerable similarities neurodegenerative diseases and mental disorders, such asbetween the genes expressed in the developing brain and pan- Alzheimer’s disease, dementia, and depression, adult neurogen-creas in mammals (Habener et al., 2005; Hori et al., 2005). esis declines more significantly. This indicates that adult neuro-Despite their separate developmental origins, the gene expres- genesis is regulated by a molecular mechanism that can vary assion programs for developing neurons and b cells are remarkably a result of both external stimuli and the biological environmentsimilar (Habener et al., 2005). in which an individual lives. In the first stage, during the neuronal differentiation from adult In diabetes, deficits in insulin secretion influence the pancreaticNSCs, early committed neuronal progenitors transiently express endocrine system and the neuronal function within the brain.BETA2/neurogenic differentiation protein (NeuroD). NeuroD, a Both type 1 and type 2 diabetes are characterized by markedmember of the basic helix-loop-helix family of transcription reductions in Wnt3 expression in the pancreas and the brainfactors, plays an essential role in both the pancreas and the (Kuwabara et al., 2011). A family of IGF-binding proteins (Firthbrain (Naya et al., 1997; Miyata et al., 1999; Liu et al., 2000). A and Baxter, 2002) modulates the bioactivity of IGF and impairsNeuroD deficiency in mice causes severe diabetes and perinatal Wnt/b-catenin signaling (Zhu et al., 2008); the most potent Wntlethality because NeuroD is required for insulin gene expression inhibitor is the insulin-like growth factor-binding protein-4(Naya et al., 1997). The adenovirus-mediated introduction of (IGFBP-4; Zhu et al., 2008). In diabetes, IGFBP-4 is upregulatedNeuroD can also induce ectopic insulin expression in the liver in both the adult brain and the pancreas, suggesting that the(Kojima et al., 2003). Noguchi et al. (2005) demonstrated that balance between the stimulatory actions of Wnt3 and the inhibi-the NeuroD protein permeates several cells and enhances the tory actions of IGFBP-4 is regulated by the diabetes status.insulin promoter activity. Protein therapy with NeuroD proteins Interestingly, Wnt3 expression is detected in pancreatic a cellshas been shown to alleviate the symptoms of diabetes mellitus together with the GFAP astrocytic marker, again indicating thein vivo via enhancing insulin expression (Huang et al., 2007). similarity of gene regulation between the CNS and the pancreas. A NeuroD deficiency during hippocampal development leads to Physiologically induced changes (such as those during diabetes)the complete loss of the dentate gyrus (where neurogenesis in Wnt3 and IGFBP-4 expression might reflect the changes occur-occurs and NSCs reside) formation in mice (Miyata et al., 1999; ring in specific niches in both the pancreas and the adult CNS.Liu et al., 2000). NeuroD1-positive cells are clearly detected inearly-stage neurons in the SGZ region of the dentate gyrus and Autologous NSC therapy for diabetesnever co-localize with Sox2-expressing NSCs (Kuwabara et al., For autologous cells to have a potential application in regenera-2009). An inducible adult NSC-specific deletion of NeuroD in tive medicine, the cells must be collected from a suitable source. Antransgenic mice results in substantially fewer newly differentiated endoscopic collection of multipotent NSCs from the olfactory bulb isneurons in the hippocampus and olfactory bulb (Gao et al., 2009), obviously preferable to the surgical collection of intracerebellarsuggesting that NeuroD is a critical regulator of adult neurogen- NSCs through a difficult and risky surgery. Adult NSCs collectedesis. Consistent with the proneural expression of NeuroD during from both the hippocampus and the olfactory bulbs of diabeticadult neurogenesis (Gao et al., 2009; Kuwabara et al., 2009), rats were transplanted back into diabetic rats after increasing thewe recently demonstrated that insulin was expressed in insulin expression capability of the NSCs by ex vivo culture withneurons in the hippocampus and olfactory bulb, and that the recombinant Wnt3 protein and antibody against IGFBP-4.NeuroD activates insulin expression (Supplementary Figure S1). Grafted cells started to express the several key characteristics of Insulin expression levels are comparatively lower in neurons pancreatic b cells (including Ptf1a and MafA), suggesting thatthan in pancreatic islets, suggesting that other enhancer(s) are grafted NSCs respond to the niche signals in the pancreas andpresent in pancreatic endocrine lineages that function to help in- unleash their intrinsic ability to express the critical regulators ofcrease insulin expression (Kuwabara et al., 2011). pancreatic insulin production. Grafted NSCs survived over a pro- longed period and the transplant-derived neurons continued toNiches supporting insulin expression via NeuroD in adult NSCs produce insulin even 10 weeks after their transplantation; the NeuroD1 has been shown to be dependent on the canonical insulin was bioactive, resulting in reduced blood glucose levelsWnt/b-catenin activation and the removal of Sox2 repression (Kuwabara et al., 2011). Removing the grafted cell sheets fromfrom the NeuroD promoter in a sequence-specific manner the recipient animals 15–19 weeks after transplantation led to aduring adult neurogenesis (Kuwabara et al., 2009). Further, rise in their blood glucose levels again, indicating that transplantingWnt/b-catenin signaling is necessary to trigger the neuronal dif- NSCs into the pancreas could be an effective treatment for diabetes.ferentiation of adult NSCs (Lie et al., 2005). The cells comprising The transplantation strategy (Figure 2) does not require thethe bottom layer of the hippocampal granule neuron layer are introduction of any inductive genes and confirms that there is acalled astrocytes and they produce Wnt3/Wnt3a and, therefore, strong functional similarity between adult neurons and endocrineplay an important, paracrine-like role in controlling adult b cells. It will be essential to validate these results with the
  4. 4. 4 | Journal of Molecular Cell Biology Kuwabara and Asashimaavailable human NSC lines as well as patient-derived olfactory islet endocrine cell lineages. The basic strategy outlined shouldbulb NSCs. Adult NSCs possess the intrinsic ability to generate be useful for the preliminary treatment of diabetes using theinsulin-producing cells via Wnt/b-catenin signaling, and various patient’s own NSCs before the disease progresses.studies have emphasized the presence of conserved Wnt signal-ing networks and their niches among developmentally distinct Modeling pathogenesis using various types of stem cells fromtissues. The use of adult NSCs for treating diabetes is potentially patientsadvantageous because donors are not required, the introduction Adult neurogenesis is also modulated in neurological diseasesof inductive genes is not necessary, and extracellular and en- and disorders like Alzheimer’s disease, depression, epilepsy, anddogenous regulation suitably resembles that employed by adult Huntington and Parkinson diseases. Although it is relatively easy to extract and to analyze the adult stem cells from some organs and tissues, including the liver, skin, fat, and bone marrow, in a living individual, it is extremely difficult to obtain NSCs/progeni- tors or biopsy material from the hippocampus. It is also possible to perform research on basic molecular mechanisms by combin- ing adult NSC culture systems with animal experimentation. However, it is virtually impossible to analyze living adult hippo- campal NSCs from patients with psychiatric/mental disorders, or to analyze the processes, for example, by which differentiated neurons or glial cells function and the intercellular responses to changes during progression to the disease state. To overcome these issues, research using iPSCs from patients with a variety of neuropsychiatric/mental disorders were per- formed. Established iPSCs from patients were differentiated into neurons and compared with neurons derived from iPSCs estab- lished from healthy human subjects. Whether or not specific causative genes, previously identified in animal-based studies, actually contribute to functional abnormalities in iPS neurons derived from diseased human tissue has been investigated and confirmed in several diseases, including spinal muscular atrophy, familial dysautonomia, Rett syndrome, and schizophre-Figure 2 Schematic representation of regenerative therapy for dia-betes using autologous adult NSCs. Adult NSCs are extracted from nia (SZ; Ebert et al., 2009; Lee et al., 2009; Marchetto et al.,the olfactory bulb surgically using an endoscope. Because NSCs in 2010). When neurons were transformed from cultured patient-diabetic animals had been found to contain higher IGFBP-4 (the specific iPSCs, the iPS-derived neurons made fewer connections,Wnt inhibitor) and lower levels of Wnt3/Wnt3a (activators for or synapses, with other neurons from people without mental dis-insulin production via the NeuroD activation) than that in wild-type orders. A mitigating/repairing effect on patient iPS-derivedanimals (Kuwabara et al., 2011), treating the cultured NSCs with neurons was actually seen when clinical reagents for SZ patientsWnt3/Wnt3a ligands and anti-IGFBP-4 (neutralizing antibody were added in the culture dish (Brennand et al., 2011). iPS cellagainst the IGFBP-4 protein) rescues insulin expression during ex lines from multiple patients and controls will need to be com-vivo culture on the collagen sheets. pared for their responses in order to investigate the variabilityFigure 3 Modeling pathogenesis using iPSCs and adult NSCs from patients of mental disorders. Established iPSCs from patient’s skin or theadult NSCs from the olfactory bulb reconsisting the process to give treatment may become available.
  5. 5. Regenerative medicine using adult neural stem cells Journal of Molecular Cell Biology | 5due to the individual donor and the disease status. naturally. Thus, there appears to be enormous potential for the On the other hand, differences between cells derived from use of NSCs, derived from tissues that are comparatively easypatients with mental disorders and those from healthy people to harvest, in both regenerative medicine and in pharmaceuticalcould reflect changes brought about by the process of creating testing.iPSCs with the four exogenous gene products (Oct4, Klf4,c-Myc, and Sox2) and not the disease itself. Since human iPSCsshare many characteristics with human ESCs, differentiated Supplementary materialneurons derived from patient iPSCs could also reflect regulation Supplementary material is available at Journal of Molecular Cellduring the embryonic stage rather than the adult stage. The regu- Biology online.lation of NSCs during the embryonic stage is different from thatoccurring during the adult stage with regard to both the extracel- Fundinglular signals and the intracellular genetic programs. The develop- The original work described in the present review article wasment of the CNS begins as a sheet of cells made up of primary supported, in part, by the National Institute of Advancedprogenitors known as neuroepithelial cells (Merkle and Industrial Science and Technology (to M.A.), a Grant-in-Aid forAlvarez-Buylla, 2006). At the onset of CNS formation, neuroepi- Young Scientists (B) (to T.K.), and a Grant-in-Aid for Scientificthelial cells are thought to be replaced by different NSCs. The Research (A) (to T.K. and M.A.).neuroepithelial cells gradually transform to radial glial cells bychanging their morphology and producing different progeny Conflict of interest: none declared.(Wen et al., 2009). Microarray analyses and quantitative reverse transcription- Referencespolymerase chain reaction analyses of NSCs derived from the Abematsu, M., Smith, I., and Nakashima, K. (2006). Mechanisms of neural stemadult hippocampus and the olfactory bulb have revealed that cell fate determination: extracellular cues and intracellular programs. NSCs from the olfactory bulb share many characteristics Stem Cell Res. Ther. 1, 267– 277. Aberg, M.A., Aberg, N.D., Hedbacker, H., et al. (2000). Peripheral infusion ofwith NSCs from the adult hippocampus. Both olfactory bulb and IGF-I selectively induces neurogenesis in the adult rat hippocampus.hippocampal NSCs responded similarly, and in a dose-dependent J. Neurosci. 20, 2896 –2903.manner, to exposure to exogenous ligands and chemical reagents Aberg, M.A., Aberg, N.D., Palmer, T.D., et al. (2003). IGF-I has a direct proliferative(Kuwabara et al., 2011). Results such as these open up the pos- effect in adult hippocampal progenitor cells. Mol. Cell Neurosci. 24, 23–40.sibility of screening drugs using adult NSCs derived from the Arsenijevic, Y., Weiss, S., Schneider, B., et al. (2001). Insulin-like growth factor-I is necessary for neural stem cell proliferation and demonstrates dis-patient’s own olfactory bulb (Figure 3). tinct actions of epidermal growth factor and fibroblast growth factor-2. If such experimental systems are used, they may be applied to J. Neurosci. 21, 7194 – 7202.the drug discovery screening that involves cells that are function- Asashima, M., Nakano, H., Shimada, K., et al. (1990). Mesodermal induction inally similar to those that comprise tissues that are difficult to early amphibian embryos by activin A (erythroid differentiation factor).access. Beyond that, it may be possible to provide ‘made-to- Roux’s Arch. Dev. Biol. 198, 330– 335. Asashima, M., Michiue, T., and Kurisaki, A. (2008). Elucidation of the role oforder’ disease treatments (personalized treatments) adapted to activin in organogenesis using a multiple organ induction system with am-individual differences (Figure 3). phibian and mouse undifferentiated cells in vitro. Dev. Growth Differ. 50, S35 –S45.Conclusions Asashima, M., Ito, Y., Chan, T., et al. (2009). In vitro organogenesis from undif- Various cell-based approaches have been explored for diabetes ferentiated cells in Xenopus. Dev. Dyn. 238, 1309– 1320.treatment: (i) differentiation to the b cell lineage from ESCs and/ Baker, M. (2007). Adult cells reprogrammed to pluripotency, without tumors. Nat Rep Stem Cells.or iPSCs (Kajiyama et al., 2000; Moriya et al., 2000; Lumelsky Basak, O., and Taylor, V. (2009). Stem cells of the adult mammalian brain andet al., 2001; Nakanishi et al., 2007; Tateishi et al., 2008), (ii) a their niche. Cell Mol. 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