• International Journal of Oral Biology
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• 제33권2호
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• pp.59-64
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• 2008

This study was designed to investigate the changes in the properties of the neuronal setm cells or progenitor cells associated with age-related decline in neurogenesis of the hippocampal dentate gyrus (DG). Active whole cells cycle marker Ki67 (a marker of whole cell cycle)-positive and S phase marker bromodeoxyuridine (BrdU)-positive. Neural stem cells gradually were reduced in the hippocampal subgranular zone (SGZ) in an age-dependant manner after birth (from P1 month to P1 year). The ratio of BrdUpositivecells/Ki67-positive cells was gradually enhanced in an age-dependent manner. The ratio of Ki67-positive cells/accu-mulating BrdU-positive cells at 3 hrs after BrdU injection was injected once a day for consecutive 5 days gradually decreased during ageing. TUNEL- and caspase 3 (apoptotic terminal caspase)-positive cells gradually decreased in the dentate SGZ during ageing and immunohistochemical findings of glial fibrillary acid protein (GFAP) were not changed during ageing. NeuN, a marker of mature neural cells, and BrdU-double positive cells gradually decreased in an age-dependent manner but differentiating ratio and survival rate of cells were not changed at 4 wks after BrdU injection once a day for consecutive 5 days. The number of BrdU-positive cells migrated from the hippocampal SGZ into granular layer and its migration speed was gradually declined during ageing. These results suggest that the adult neurogenesis in the mouse hippocampal DG gradually decrease through reducing proliferation of neural stem cells accompanying with cells cycle change and reduced cells migration rather than changes of differentiation.

• BMB Reports
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• 제35권1호
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• pp.87-93
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• 2002

Neural cell survival is an essential concern in the aging brain and many diseases of the central nervous system. Neural transplantation of the stem cells are already applied to clinical trials for many degenerative neurological diseases, including Huntington's disease, Parkinson's disease, and strokes. A critical problem of the neural transplantation is how to reduce their apoptosis and improve cell survival. Neurotrophic factors generally contribute as extrinsic cues to promote cell survival of specific neurons in the developing mammalian brains, but the survival factor for neural stem cell is poorly defined. To understand the mechanism controlling stem cell death and improve cell survival of the transplanted stem cells, we investigated the effect of plausible neurotrophic factors on stem cell survival. The neural stem cell, HiB5, when treated with PDGF prior to transplantation, survived better than cells without PDGF. The resulting survival rate was two fold for four weeks and up to three fold for twelve weeks. When transplanted into dorsal hippocampus, they migrated along hippocampal alveus and integrated into pyramidal cell layers and dentate granule cell layers in an inside out sequence, which is perhaps the endogenous pathway that is similar to that in embryonic neurogenesis. Promotion of the long term-survival and differentiation of the transplanted neural precursors by PDGF may facilitate regeneration in the aging adult brain and probably in the injury sites of the brain.

• BMB Reports
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• 제57권4호
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• pp.182-187
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• 2024

Neural stem cells (NSCs) in the adult hippocampus divide infrequently; the endogenous molecules modulating adult hippocampal neurogenesis (AHN) remain largely unknown. Here, we show that ErbB3 binding protein 1 (Ebp1), which plays important roles in embryonic neurodevelopment, acts as an essential modulator of adult neurogenic factors. In vivo analysis of Ebp1 neuron depletion mice showed impaired AHN with a low number of hippocampal NSCs and neuroblasts. Ebp1 leads to transcriptional repression of Bmp4 and suppression of Ascl1 promoter methylation in the dentate gyrus of the adult hippocampus reflecting an unusually high level of Bmp4 and low Ascl1 level in neurons of Ebp1-deficient mice. Therefore, our findings suggests that Ebp1 could act as an endogenous modulator of the interplay between Bmp4 and Ascl1/Notch signaling, contributing to AHN.

• Applied Microscopy
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• 제42권4호
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• pp.200-206
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• 2012

Induction of neurogenesis can occur in the hippocampus in response to various pathological conditions, such as Alzheimer's disease. The aim of this study was to investigate the changes that occur in endogenous neural stem cells in response to amyloid beta $(A{\beta})_{25-35}$-induced neuronal cell damage in organotypic hippocampal slice cultures. Cresyl violet staining and Fluoro-Jade B staining were used to detect neuronal cell damage and changes of mossy fiber terminals were observed by Timm's staining. The immunofl uorescence staining was used to detect the newly generated cells in the subgranular zone (SGZ) of the dentate gyrus with specific marker, 5-bromo-2'-deoxyuridine (BrdU), Ki-67, Nestin, and doublecortin (DCX). In compared to control slices, neuronal cell damage was observed and the mossy fibers were expanded to CA3 area by treatment with $A{\beta}_{25-35}$. Ki-67/Nestin- and BrdU/DCX-positive cells were detected in the SGZ. In conclusion, these results demonstrate that $A{\beta}$-induced neuronal damage results in an increase in endogenous neural stem cells in rat hippocampal slice cultures not only for gliosis but also for neurogenesis.

• BMB Reports
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• 제46권8호
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• pp.383-390
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• 2013

Mammalian neural stem cells (NSCs) are of particular interest because of their role in brain development and function. Recent findings suggest the intimate involvement of programmed cell death (PCD) in the turnover of NSCs. However, the underlying mechanisms of PCD are largely unknown. Although apoptosis is the best-defined form of PCD, accumulating evidence has revealed a wide spectrum of PCD encompassing apoptosis, autophagic cell death (ACD) and necrosis. This mini-review aims to illustrate a unique regulation of PCD in NSCs. The results of our recent studies on autophagic death of adult hippocampal neural stem (HCN) cells are also discussed. HCN cell death following insulin withdrawal clearly provides a reliable model that can be used to analyze the molecular mechanisms of ACD in the larger context of PCD. More research efforts are needed to increase our understanding of the molecular basis of NSC turnover under degenerating conditions, such as aging, stress and neurological diseases. Efforts aimed at protecting and harnessing endogenous NSCs will offer novel opportunities for the development of new therapeutic strategies for neuropathologies.

• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.145-153
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• 2018

The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury, the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdU-positive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved-caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double-positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain.

• BMB Reports
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• 제57권6호
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• pp.281-286
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• 2024

Adult hippocampal neurogenesis plays a pivotal role in maintaining cognitive brain function. However, this process diminishes with age, particularly in patients with neurodegenerative disorders. While small, non-coding microRNAs (miRNAs) are crucial for hippocampal neural stem (HCN) cell maintenance, their involvement in neurodegenerative disorders remains unclear. This study aimed to elucidate the mechanisms through which miRNAs regulate HCN cell death and their potential involvement in neurodegenerative disorders. We performed a comprehensive microarray-based analysis to investigate changes in miRNA expression in insulin-deprived HCN cells as an in vitro model for cognitive impairment. miR-150-3p, miR-323-5p, and miR-370-3p, which increased significantly over time following insulin withdrawal, induced pronounced mitochondrial fission and dysfunction, ultimately leading to HCN cell death. These miRNAs collectively targeted the mitochondrial fusion protein OPA1, with miR-150-3p also targeting MFN2. Data-driven analyses of the hippocampi and brains of human subjects revealed significant reductions in OPA1 and MFN2 in patients with Alzheimer's disease (AD). Our results indicate that miR-150-3p, miR-323-5p, and miR-370-3p contribute to deficits in hippocampal neurogenesis by modulating mitochondrial dynamics. Our findings provide novel insight into the intricate connections between miRNA and mitochondrial dynamics, shedding light on their potential involvement in conditions characterized by deficits in hippocampal neurogenesis, such as AD.

• Molecules and Cells
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• 제39권8호
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• pp.603-610
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• 2016

Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.

• BMB Reports
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• 제44권12호
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• pp.793-798
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• 2011

Recently, pluripotency induction or cellular reprogramming by introducing critical transcription factors has been extensively studied, but has been demonstrated only in vitro. Based on reports that Oct4 is critically involved in transforming neural stem cells into pluripotent cells, we used the lentiviral vector to introduce the Oct4 gene into the hippocampal dentate gyrus (DG) of adult mice. We examined whether this manipulation led to cellular or behavioral changes, possibly through processes involving the transformation of NS cells into pluripotent cells. The Oct4 lentivirus-infused group and the green fluorescent protein lentivirus-infused group showed a similar thickness of the DG and a comparable level of synaptophysin expression in the DG. Furthermore, our behavioral analyses did not show any differences between the groups concerning exploratory activity, anxiety, or memory abilities. This first trial for pluripotency induction in vivo, despite negative results, provides implications and information for future studies on in vivo cellular reprogramming.