{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T16:06:13Z","timestamp":1787933173041,"version":"build-2784847793"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2010,3,3]],"date-time":"2010-03-03T00:00:00Z","timestamp":1267574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Ministry of Science and Technology, Republic of Korea"},{"name":"Korean Ministry of Education, Science and Technology"},{"name":"Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea","award":["A084065"],"award-info":[{"award-number":["A084065"]}]},{"DOI":"10.13039\/501100004085","name":"Ministry of Education, Science and Technology","doi-asserted-by":"crossref","award":["2009-0081959"],"award-info":[{"award-number":["2009-0081959"]}],"id":[{"id":"10.13039\/501100004085","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Niemann-Pick type C (NP-C) disease exhibits neuronal sphingolipid storage and cerebellar Purkinje neuron (PN) loss. Although it is clear that PNs are compromised in this disorder, it remains to be defined how neuronal lipid storage causes the PN loss. Our previous studies have shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation prevent PN loss in NP-C mice. The aim of the present study was therefore to examine the neuroprotective mechanism of BM-MSCs on PNs. We found that NP-C PNs exhibit abnormal sphingolipid metabolism and defective lysosomal calcium store compared to wild-type mice PNs. BM-MSCs promote the survival of NP-C PNs by correction of the altered calcium homeostasis, restoration of the sphingolipid imbalance, as evidenced by increased sphingosine-1-phosphate levels and decreased sphingosine, and ultimately, inhibition of apoptosis pathways. These effects suggest that BM-MSCs modulate sphingolipid metabolism of endogenous NP-C PNs, resulting in their survival and improved clinical outcome in mice.<\/jats:p>","DOI":"10.1002\/stem.401","type":"journal-article","created":{"date-parts":[[2010,3,3]],"date-time":"2010-03-03T20:32:42Z","timestamp":1267648362000},"page":"821-831","source":"Crossref","is-referenced-by-count":53,"title":["Bone Marrow-Derived Mesenchymal Stem Cells Prevent the Loss of Niemann-Pick Type C Mouse Purkinje Neurons by Correcting Sphingolipid Metabolism and Increasing Sphingosine-1-phosphate"],"prefix":"10.1093","volume":"28","author":[{"given":"Hyun","family":"Lee","sequence":"first","affiliation":[{"name":"Stem Cell Neuroplasticity Research Group, Daegu, Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, BSEI, World Class University Program, School of Medicine, Daegu, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Kil","family":"Lee","sequence":"additional","affiliation":[{"name":"Stem Cell Neuroplasticity Research Group, Daegu, Korea"},{"name":"Department of Laboratory Animal Medicine, Cell and Matrix Research Institute, College of Veterinary Medicine, Daegu, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo-Kie","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Kyungpook National University Hospital, Daegu, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hoon","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Keimyung University, Daegu, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxuan","family":"He","sequence":"additional","affiliation":[{"name":"Departments of Genetics and Genomic Sciences & Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward H.","family":"Schuchman","sequence":"additional","affiliation":[{"name":"Departments of Genetics and Genomic Sciences & Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-sung","family":"Bae","sequence":"additional","affiliation":[{"name":"Stem Cell Neuroplasticity Research Group, Daegu, Korea"},{"name":"Department of Physiology, Cell and Matrix Research Institute, BSEI, World Class University Program, School of Medicine, Daegu, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Kyung","family":"Jin","sequence":"additional","affiliation":[{"name":"Stem Cell Neuroplasticity Research Group, Daegu, Korea"},{"name":"Department of Laboratory Animal Medicine, Cell and Matrix Research Institute, College of Veterinary Medicine, Daegu, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,3,3]]},"reference":[{"key":"2022011217430432300_bib1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1750-3639.1998.tb00143.x","article-title":"Recent advances in elucidating Niemann-Pick C disease","volume":"8","author":"Vanier","year":"1998","journal-title":"Brain Pathol"},{"key":"2022011217430432300_bib2","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1006\/bbrc.1993.2228","article-title":"Niemann-Pick C disease: cystine and lipids accumulate in the murine model of this lysosomal cholesterol lipidosis","volume":"196","author":"Butler","year":"1993","journal-title":"Biochem Biophys Res Commun"},{"key":"2022011217430432300_bib3","doi-asserted-by":"crossref","first-page":"26167","DOI":"10.1074\/jbc.M311591200","article-title":"Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport","volume":"279","author":"te Vruchte","year":"2004","journal-title":"J Biol Chem"},{"key":"2022011217430432300_bib4","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1097\/00005072-198805000-00008","article-title":"Cerebellar involvement in murine sphingomyelinosis: a new model of Niemann-Pick disease","volume":"47","author":"Tanaka","year":"1988","journal-title":"J Neuropathol Exp Neurol"},{"key":"2022011217430432300_bib5","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.bbalip.2004.08.011","article-title":"Consequences of NPC1 and NPC2 loss of function in mammalian neurons","volume":"1685","author":"Walkley","year":"2004","journal-title":"Biochim Biophys Acta"},{"key":"2022011217430432300_bib6","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1126\/science.277.5323.228","article-title":"Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis","volume":"277","author":"Carstea","year":"1997","journal-title":"Science"},{"key":"2022011217430432300_bib7","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1038\/nm.1876","article-title":"Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium","volume":"14","author":"Lloyd-Evans","year":"2008","journal-title":"Nat Med"},{"key":"2022011217430432300_bib8","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1002\/jnr.21586","article-title":"Multifaceted roles of sphingosine-1-phosphate: how does this bioactive sphingolipid fit with acute neurological injury?","volume":"86","author":"Singh","year":"2008","journal-title":"J Neurosci Res"},{"key":"2022011217430432300_bib9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ymgme.2004.08.017","article-title":"Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease","volume":"84","author":"Wu","year":"2005","journal-title":"Mol Genet Metab"},{"key":"2022011217430432300_bib10","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1093\/jnen\/64.4.323","article-title":"Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease","volume":"64","author":"Li","year":"2005","journal-title":"J Neuropathol Exp Neurol"},{"key":"2022011217430432300_bib11","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1089\/hum.2005.16.1006","article-title":"Neurodegeneration augments the ability of bone marrow-derived mesenchymal stem cells to fuse with Purkinje neurons in Niemann-Pick type C mice","volume":"16","author":"Bae","year":"2005","journal-title":"Hum Gene Ther"},{"key":"2022011217430432300_bib12","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1634\/stemcells.2006-0561","article-title":"Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration","volume":"25","author":"Bae","year":"2007","journal-title":"Stem Cells"},{"key":"2022011217430432300_bib13","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1126\/science.277.5323.232","article-title":"Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene","volume":"277","author":"Loftus","year":"1997","journal-title":"Science"},{"key":"2022011217430432300_bib14","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S1385-299X(98)00040-3","article-title":"An improved method for culturing cerebellar Purkinje cells with differentiated dendrites under a mixed monolayer setting","volume":"3","author":"Furuya","year":"1998","journal-title":"Brain Res Protoc"},{"key":"2022011217430432300_bib15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0165-0270(00)00323-X","article-title":"A reliable method for culture of dissociated mouse cerebellar cells enriched for Purkinje neurons","volume":"104","author":"Tabata","year":"2000","journal-title":"J Neurosci Methods"},{"key":"2022011217430432300_bib16","first-page":"3791","article-title":"Isolation and culture of post-natal mouse cerebellar granule neuron progenitor cells and neurons","volume":"10","author":"Lee","year":"2009","journal-title":"J Vis Exp"},{"key":"2022011217430432300_bib17","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ab.2005.01.058","article-title":"Simultaneous quantitative analysis of ceramide and sphingosine in mouse blood by naphthalene-2, 3-dicarboxyaldehyde derivatization after hydrolysis with ceramidase","volume":"340","author":"He","year":"2005","journal-title":"Anal Biochem"},{"key":"2022011217430432300_bib18","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1242\/jcs.115.3.599","article-title":"pH-dependent regulation of lysosomal calcium in macrophages","volume":"115","author":"Christensen","year":"2002","journal-title":"J Cell Sci"},{"key":"2022011217430432300_bib19","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1006\/bbrc.2002.6372","article-title":"EGCG attenuates AMPA-induced intracellular calcium increase in hippocampal neurons","volume":"290","author":"Bae","year":"2002","journal-title":"Biochem Biophys Res Commun"},{"key":"2022011217430432300_bib20","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neulet.2005.02.029","article-title":"Neuroglial activation in Niemann-Pick Type C mice is suppressed by intraral transplantation of bone marrow-derived mesenchymal stem cells","volume":"381","author":"Bae","year":"2005","journal-title":"Neurosci Lett"},{"key":"2022011217430432300_bib21","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/S0014-4886(03)00345-5","article-title":"Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: immunohistochemical observations of microglia and astroglia","volume":"184","author":"Baudry","year":"2003","journal-title":"Exp Neurol"},{"key":"2022011217430432300_bib22","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1016\/j.bbamem.2006.08.007","article-title":"Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases","volume":"1758","author":"Hait","year":"2006","journal-title":"Biochim Biophys Acta"},{"key":"2022011217430432300_bib23","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.bbrc.2005.12.138","article-title":"Regulation by sphingosine 1-phosphate of Bax and Bad activities during apoptosis in a MEK-dependent manner","volume":"340","author":"Betito","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"2022011217430432300_bib24","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1182\/blood-2006-04-014852","article-title":"Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate","volume":"108","author":"Weigert","year":"2006","journal-title":"Blood"},{"key":"2022011217430432300_bib25","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nbt1119","article-title":"Stem and progenitor cell-based therapy of the human central nervous system","volume":"23","author":"Goldman","year":"2005","journal-title":"Nat Biotechnol"},{"key":"2022011217430432300_bib26","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.molbrainres.2004.09.002","article-title":"Stem cells may reshape the prospect of Parkinson's disease therapy","volume":"134","author":"Sonntag","year":"2005","journal-title":"Brain Res Mol Brain Res"},{"key":"2022011217430432300_bib27","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.brainres.2006.01.073","article-title":"The promise of stem cells for neural repair","volume":"1091","author":"Miller","year":"2006","journal-title":"Brain Res"},{"key":"2022011217430432300_bib28","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1038\/81395","article-title":"Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep","volume":"6","author":"Liechty","year":"2000","journal-title":"Nat Med"},{"key":"2022011217430432300_bib29","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1073\/pnas.0336479100","article-title":"Transplanted bone marrow generates new neurons in human brains","volume":"100","author":"Mezey","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011217430432300_bib30","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1073\/pnas.0337659100","article-title":"Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains","volume":"100","author":"Weimann","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011217430432300_bib31","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/sj.bmt.1705757","article-title":"Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury","volume":"40","author":"Parr","year":"2007","journal-title":"Bone Marrow Transplant"},{"key":"2022011217430432300_bib32","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/sj.clpt.6100313","article-title":"\u201cStemness\u201d does not explain the repair of many tissues by mesenchymal stem\/multipotent stromal cells (MSCs)","volume":"82","author":"Prockop","year":"2007","journal-title":"Clin Pharmacol Ther"},{"key":"2022011217430432300_bib33","doi-asserted-by":"crossref","first-page":"18171","DOI":"10.1073\/pnas.0508945102","article-title":"Human stem\/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice","volume":"102","author":"Munoz","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"Suppl 1","key":"2022011217430432300_bib34","doi-asserted-by":"crossref","first-page":"11917","DOI":"10.1073\/pnas.1834138100","article-title":"One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues","volume":"100","author":"Prockop","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022011217430432300_bib35","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.bbrc.2007.01.045","article-title":"Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment","volume":"354","author":"Iso","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"2022011217430432300_bib36","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1023\/A:1022575511354","article-title":"Lipid changes in Niemann-Pick disease type C brain: personal experience and review of the literature","volume":"24","author":"Vanier","year":"1999","journal-title":"Neurochem Res"},{"key":"2022011217430432300_bib37","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.cellsig.2007.12.006","article-title":"The sphingolipid salvage pathway in ceramide metabolism and signaling","volume":"20","author":"Kitatani","year":"2008","journal-title":"Cell Signal"},{"key":"2022011217430432300_bib38","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cellsig.2008.07.011","article-title":"Sphingosine kinase\/sphingosine 1-phosphate signalling in central nervous system","volume":"21","author":"Okada","year":"2009","journal-title":"Cell Signal"},{"key":"2022011217430432300_bib39","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/BF00227765","article-title":"Cerebellar degeneration in the Niemann-Pick type C mouse","volume":"85","author":"Higashi","year":"1993","journal-title":"Acta Neuropathol"},{"key":"2022011217430432300_bib40","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s002210100870","article-title":"Neurodegeneration in Niemann-Pick type C disease mice","volume":"141","author":"Ong","year":"2001","journal-title":"Exp Brain Res"},{"key":"2022011217430432300_bib41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1083\/jcb.114.1.155","article-title":"Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation","volume":"114","author":"Zhang","year":"1991","journal-title":"J Cell Biol"},{"key":"2022011217430432300_bib42","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/381800a0","article-title":"Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate","volume":"381","author":"Cuvillier","year":"1996","journal-title":"Nature"},{"key":"2022011217430432300_bib43","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nrn1725","article-title":"Storage solutions: treating lysosomal disorders of the brain","volume":"6","author":"Jeyakumar","year":"2005","journal-title":"Nat Rev Neurosci"},{"key":"2022011217430432300_bib44","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0005-2736(94)90007-8","article-title":"Sphingosine regulates Ca(2+)-ATPase and reloading of intracellular Ca2+ stores in the pancreatic acinar cell","volume":"1195","author":"Pandol","year":"1994","journal-title":"Biochim Biophys Acta"},{"key":"2022011217430432300_bib45","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/365557a0","article-title":"Sphingosine-1-phosphate as a second messenger in cell proliferation induced by PDGF and FCS mitogens","volume":"365","author":"Olivera","year":"1993","journal-title":"Nature"},{"key":"2022011217430432300_bib46","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1749-6632.1998.tb09658.x","article-title":"Sphingosine-1-phosphate in cell growth and cell death","volume":"845","author":"Spiegel","year":"1998","journal-title":"Ann NY Acad Sci"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.401","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.401","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.401","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/28\/4\/821\/41951329\/stmcls_28_4_821.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/28\/4\/821\/41951329\/stmcls_28_4_821.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T03:04:51Z","timestamp":1642561491000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/28\/4\/821-831\/6400602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3,3]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2010,3,3]]},"published-print":{"date-parts":[[2010,4,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.401","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2010,4,1]]},"published":{"date-parts":[[2010,3,3]]}}}