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Lee, Hyun,Lee, Jong Kil,Bae, Yong Chul,Yang, Song Hyun,Okino, Nozomu,Schuchman, Edward H.,Yamashita, Tadashi,Bae, Jae-Sung,Jin, Hee Kyung Korean Society for Molecular and Cellular Biology 2014 Molecules and cells Vol.37 No.2
In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NP-C mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.
Lee, Jong Kil,Schuchman, Edward H,Jin, Hee Kyung,Bae, Jae-sung AlphaMed Press 2012 Stem cells Vol.30 No.7
<P>Microglia have the ability to eliminate amyloid β (Aβ) by a cell-specific phagocytic mechanism, and bone marrow (BM) stem cells have shown a beneficial effect through endogenous microglia activation in the brains of Alzheimer's disease (AD) mice. However, the mechanisms underlying BM-induced activation of microglia have not been resolved. Here we show that BM-derived mesenchymal stem cells (MSCs) induced the migration of microglia when exposed to Aβ in vitro. Cytokine array analysis of the BM-MSC media obtained after stimulation by Aβ further revealed elevated release of the chemoattractive factor, CCL5. We also observed that CCL5 was increased when BM-MSCs were transplanted into the brains of Aβ-deposited AD mice, but not normal mice. Interestingly, alternative activation of microglia in AD mice was associated with elevated CCL5 expression following intracerebral BM-MSC transplantation. Furthermore, by generating an AD-green fluorescent protein chimeric mouse, we ascertained that endogenous BM cells, recruited into the brain by CCL5, induced microglial activation. Additionally, we observed that neprilysin and interleukin-4 derived from the alternative microglia were associated with a reduction in Aβ deposition and memory impairment in AD mice. These results suggest that the beneficial effects observed in AD mice after intracerebral SC transplantation may be explained by alternative microglia activation. The recruitment of the alternative microglia into the brain is driven by CCL5 secretion from the transplanted BM-MSCs, which itself is induced by Aβ deposition in the AD brain.</P>
( Jin Young Im ),( Woo Kie Min ),( Min Hee Park ),( Nam Oh Kim ),( Jong Kil Lee ),( Hee Kyung Jin ),( Je Yong Choi ),( Shin Yoon Kim ),( Jae Sung Bae ) 생화학분자생물학회(구 한국생화학분자생물학회) 2014 BMB Reports Vol.47 No.8
Inhibition of an increase of osteoclasts has become the mostimportant treatment for osteoporosis. The CXCR4 antagonist, AMD3100, plays an important role in the mobilization ofosteoclast precursors within bone marrow (BM). However, theactual therapeutic impact of AMD3100 in osteoporosis has notyet been ascertained. Here we demonstrate the therapeuticeffect of AMD3100 in the treatment of ovariectomy-inducedosteoporosis in mice. We found that treatment with AMD3100resulted in direct induction of release of SDF-1 from BM toblood and mobilization of hematopoietic stem/progenitor cells(HSPCs) in an osteoporosis model. AMD3100 prevented bonedensity loss after ovariectomy by mobilization of HSPCs, suggesting a therapeutic strategy to reduce the number ofosteoclasts on bone surfaces. These findings support thehypothesis that treatment with AMD3100 can result in efficientmobilization of HSPCs into blood through direct blockade ofthe SDF-1/CXCR4 interaction in BM and can be considered asa potential new therapeutic intervention for osteoporosis.
Lee, Jong Kil,Jin, Hee Kyung,Park, Min Hee,Kim, Bo-ra,Lee, Phil Hyu,Nakauchi, Hiromitsu,Carter, Janet E.,He, Xingxuan,Schuchman, Edward H.,Bae, Jae-sung The Rockefeller University Press 2014 The Journal of experimental medicine Vol.211 No.8
<P>In Alzheimer’s disease (AD), abnormal sphingolipid metabolism has been reported, although the pathogenic consequences of these changes have not been fully characterized. We show that acid sphingomyelinase (ASM) is increased in fibroblasts, brain, and/or plasma from patients with AD and in AD mice, leading to defective autophagic degradation due to lysosomal depletion. Partial genetic inhibition of ASM (<I>ASM<SUP>+/−</SUP></I>) in a mouse model of familial AD (FAD; <I>amyloid precursor protein</I> [<I>APP</I>]<I>/presenilin 1</I> [<I>PS1</I>]) ameliorated the autophagocytic defect by restoring lysosomal biogenesis, resulting in improved AD clinical and pathological findings, including reduction of amyloid-β (Aβ) deposition and improvement of memory impairment. Similar effects were noted after pharmacologic restoration of ASM to the normal range in APP/PS1 mice. Autophagic dysfunction in neurons derived from FAD patient induced pluripotent stem cells (iPSCs) was restored by partial ASM inhibition. Overall, these results reveal a novel mechanism of ASM pathogenesis in AD that leads to defective autophagy due to impaired lysosomal biogenesis and suggests that partial ASM inhibition is a potential new therapeutic intervention for the disease.</P>
Lee, Jong Kil,Chun, So Young,Im, Jin Young,Jin, Hee Kyung,Kwon, Tae Gyun,Bae, Jae-Sung The Society ; Maruzen Co. [distributor] 2012 The Journal of veterinary medical science Vol.74 No.8
<P>Stem cell based cell therapies offer significant potential for the field of regenerative medicine. Human amniotic fluid stem cells (hAFSCs) are an attractive source for lineage-specific differentiated stem cell therapy since they have properties that are able to differentiate into cells representing all three germ layers. To better understand the fate and location of implanted hAFSCs, a means to monitor cells in living subjects is essential. Here, we showed that differentiated cells, such as neurogenic, endothelial, and myogenic cells, derived from hAFSCs can be effectively labeled by the FITC-incorporated silica-coated nanoparticles, MNPs@SiO2 (FITC), although the labeling efficacy and cytotoxicity were distinct depending on the differentiated cell type. In addition, we observed that MNPs@SiO2-labeled cells provided sufficient signals for detection by optical and confocal microscope imaging when transplanted into the mice. These results suggest that the fluorescent dye incorporated MNPs@SiO2 are a useful tool for the cell labeling and in vivo tracking of differentiated cells derived from hAFSCs.</P>