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
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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)