Monitoring neurodegeneration in diabetes using adult neural stem cells derived from the olfactory bulb

Stem Cell Research & Therapy, May 2013

Introduction Neurons have the intrinsic capacity to produce insulin, similar to pancreatic cells. Adult neural stem cells (NSCs), which give rise to functional neurons, can be established and cultured not only by intracerebral collection, which requires difficult surgery, but also by collection from the olfactory bulb (OB), which is relatively easy. Adult neurogenesis in the hippocampus (HPC) is significantly decreased in diabetes patients. As a result, learning and memory functions, for which the HPC is responsible, decrease. Methods In the present study, we compared the effect of diabetes on neurogenesis and insulin expression in adult NSCs. Adult NSCs were derived from the HPC or OB of streptozotocin-induced diabetic rats. Comparative gene-expression analyses were carried out by using extracted tissues and established adult NSC cultures from the HPC or OB in diabetic rats. Results Diabetes progression influenced important genes that were required for insulin expression in both OB- and HPC-derived cells. Additionally, we found that the expression levels of several genes, such as voltage-gated sodium channels, glutamate transporters, and glutamate receptors, were significantly different in OB and HPC cells collected from diabetic rats. Conclusions By using identified diabetes-response genes, OB NSCs from diabetes patients can be used during diabetes progression to monitor processes that cause neurodegeneration in the central nervous system (CNS). Because hippocampal NSCs and OB NSCs exhibited similar gene-expression profiles during diabetes progression, OB NSCs, which are more easily collected and established than HPC NSCs, may potentially be used for screening of effective drugs for neurodegenerative disorders that cause malignant damage to CNS functions.

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Monitoring neurodegeneration in diabetes using adult neural stem cells derived from the olfactory bulb

Stem Cell Research & Therapy Monitoring neurodegeneration in diabetes using adult neural stem cells derived from the olfactory bulb Ryo Hidaka 0 Masanao Machida 0 Shin Fujimaki Kazuyuki Terashima Makoto Asashima Tomoko Kuwabara 0 Equal contributors Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST) , Central 4, 1-1-4 Higashi, Tsukuba Science City 305-8562 , Japan Introduction: Neurons have the intrinsic capacity to produce insulin, similar to pancreatic cells. Adult neural stem cells (NSCs), which give rise to functional neurons, can be established and cultured not only by intracerebral collection, which requires difficult surgery, but also by collection from the olfactory bulb (OB), which is relatively easy. Adult neurogenesis in the hippocampus (HPC) is significantly decreased in diabetes patients. As a result, learning and memory functions, for which the HPC is responsible, decrease. Methods: In the present study, we compared the effect of diabetes on neurogenesis and insulin expression in adult NSCs. Adult NSCs were derived from the HPC or OB of streptozotocin-induced diabetic rats. Comparative gene-expression analyses were carried out by using extracted tissues and established adult NSC cultures from the HPC or OB in diabetic rats. Results: Diabetes progression influenced important genes that were required for insulin expression in both OB- and HPC-derived cells. Additionally, we found that the expression levels of several genes, such as voltage-gated sodium channels, glutamate transporters, and glutamate receptors, were significantly different in OB and HPC cells collected from diabetic rats. Conclusions: By using identified diabetes-response genes, OB NSCs from diabetes patients can be used during diabetes progression to monitor processes that cause neurodegeneration in the central nervous system (CNS). Because hippocampal NSCs and OB NSCs exhibited similar gene-expression profiles during diabetes progression, OB NSCs, which are more easily collected and established than HPC NSCs, may potentially be used for screening of effective drugs for neurodegenerative disorders that cause malignant damage to CNS functions. Neural stem cells; Hippocampus; Olfactory bulb; Diabetes; Insulin - Introduction Adult neuronal stem cells (NSCs) exist in the hippocampus (HPC), which is responsible for learning and memory, and new neurons are continuously generated, even in the adult brain [1-3]. Adult NSCs retain the selfrenewal ability characteristic of stem cells and can give rise to three differentiation lineages: neurons, astrocytes, and oligodendrocytes [4,5]. As shown in recent studies, the typical neurogenic regions in the mammalian brain are the HPC, the subventricular zone (SVZ), and the olfactory bulb (OB), and adult NSC cultures can be established from these regions. NSCs derived from the OB have the potential to be used in therapeutic applications because they are easily harvested without harm to the patient [6,7]. The fate of multipotent NSCs is determined by diverse extracellular signals, corresponding intrinsic transcriptional factors, and epigenetic machineries. Insulin is an important neuromodulator, contributing to neurobiologic processes, energy homeostasis, and cognitive function. Moreover, insulin increases the tolerance of mature neurons to toxicity and has a protective function that keeps the network functions of the neurons in an active state [8,9]. Insulin plays a major role in controlling the differentiation fate of NSCs. Insulin also promotes the induction of undifferentiated NSCs to differentiate into oligodendrocytes, which function in protecting neurons [10]. Moreover, insulin promotes the function of fibroblast growth factor 2 (FGF-2), which has an important role in maintaining NSCs in the undifferentiated state, and also plays a major role in the stem cell self-renewal stage (that is, it strongly activates stem cell proliferation [1,11-14]). In the presence of low levels of insulin, the proliferative functions of undifferentiated stem cells are suppressed in many organs. Insulin-mediated signal transduction regulates multiple roles in the self-renewal and differentiation pathways of adult stem cells. Diabetes impairs the function of hematopoietic stem cells [15], skeletal muscle stem cells (satellite cells) [16,17], osteoblast stem cells [18], and NSCs [19,20]. The diabetes-induced reduction in adult neurogenesis has been detected mainly in the HPC, and diabetes has been associated with a decline in the cognitive functions of learning and memory. Not only are diabetes patients at increased risk of contracting neurodegenerative diseases and psychiatric disorders, such as Alzheimer disease, Parkinson disease, depression, and Huntington disease [19,21,22], but diabetes has also been experimentally shown to have a great effect on the functions of the neural circuits in the HPC [8,23,24]. Streptozotocin (STZ)-induced diabet (...truncated)


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Ryo Hidaka, Masanao Machida, Shin Fujimaki, Kazuyuki Terashima, Makoto Asashima, Tomoko Kuwabara. Monitoring neurodegeneration in diabetes using adult neural stem cells derived from the olfactory bulb, Stem Cell Research & Therapy, 2013, pp. 51, Volume 4, Issue 3, DOI: 10.1186/scrt201