{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T11:58:16Z","timestamp":1780315096601,"version":"3.54.1"},"reference-count":42,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T00:00:00Z","timestamp":1590105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study evaluated the potential of iron oxide nanoparticle-loaded human embryonic stem cell (ESC)-derived spherical neural masses (SNMs) to improve the transportation of stem cells to the brain, ameliorate brain damage from intracerebral hemorrhage (ICH), and recover the functional status after ICH under an external magnetic field of a magnet attached to a helmet. At 24 h after induction of ICH, rats were randomly separated into three experimental groups: ICH with injection of phosphate-buffered saline (PBS group), ICH with intravenous injection of magnetosome-like ferrimagnetic iron oxide nanocubes (FION)-labeled SNMs (SNMs* group), and ICH with intravenous injection of FION-labeled SNMs followed by three days of external magnetic field exposure for targeted delivery by a magnet-embedded helmet (SNMs*+Helmet group). On day 3 after ICH induction, an increased Prussian blue-stained area and decreased swelling volume were observed in the SNMs*+Helmet group compared with that of the other groups. A significantly decreased recruitment of macrophages and neutrophils and a downregulation of pro-inflammatory cytokines followed by improved neurological function three days after ICH were observed in the SNMs*+Helmet group. Hemispheric atrophy at six weeks after ICH was significantly decreased in the SNMs*+Helmet group compared with that of the PBS group. In conclusion, we have developed a targeted delivery system using FION tagged to stem cells and a magnet-embedded helmet. The targeted delivery of SNMs might have the potential for developing novel therapeutic strategies for ICH.<\/jats:p>","DOI":"10.3390\/ijms21103658","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T10:18:18Z","timestamp":1590142698000},"page":"3658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Targeted Delivery of Iron Oxide Nanoparticle-Loaded Human Embryonic Stem Cell-Derived Spherical Neural Masses for Treating Intracerebral Hemorrhage"],"prefix":"10.3390","volume":"21","author":[{"given":"Min Kyoung","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea"},{"name":"Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Jung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea"},{"name":"Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Ju","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamie","family":"Kang","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonghoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Korea"},{"name":"School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nohyun","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Advanced Materials Engineering, Kookmin University, Seoul 02707, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taeghwan","family":"Hyeon","sequence":"additional","affiliation":[{"name":"Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Korea"},{"name":"School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-sun","family":"Lim","sequence":"additional","affiliation":[{"name":"Research and Development Center, Jeil Pharmaceutical Co. Ltd., Yongin-si, Gyeonggi-do 17172, Korea"},{"name":"Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jung","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hallym University Dongtan Sacred Heart Hospital, Gyeonggi-do 14068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4182-3612","authenticated-orcid":false,"given":"Jung Hwan","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Bae","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea"},{"name":"Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung-Woo","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea"},{"name":"Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.5853\/jos.2016.00864","article-title":"Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update","volume":"19","author":"An","year":"2017","journal-title":"J. Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1161\/STR.0000000000000069","article-title":"Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association\/American Stroke Association","volume":"46","author":"Hemphill","year":"2015","journal-title":"Stroke"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1093\/brain\/awm306","article-title":"Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke","volume":"131","author":"Lee","year":"2008","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"848","DOI":"10.3892\/mmr.2012.997","article-title":"Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: Reduced apoptosis and enhanced neuroprotection","volume":"6","author":"Wang","year":"2012","journal-title":"Mol. Med. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lee, H.J., Kim, K.S., Park, I.H., and Kim, S.U. (2007). Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000156"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jns.2007.06.012","article-title":"Neural stem\/precursor cells for the treatment of ischemic stroke","volume":"265","author":"Bacigaluppi","year":"2008","journal-title":"J. Neurol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0092-8674(02)00835-8","article-title":"Directed differentiation of embryonic stem cells into motor neurons","volume":"110","author":"Wichterle","year":"2002","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fneur.2018.00034","article-title":"Potential of Stem Cell-Based Therapy for Ischemic Stroke","volume":"9","author":"Marei","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1073\/pnas.0712359105","article-title":"Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells","volume":"105","author":"Cho","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.scr.2012.05.002","article-title":"Generation of retinal pigment epithelial cells from human embryonic stem cell-derived spherical neural masses","volume":"9","author":"Cho","year":"2012","journal-title":"Stem Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1002\/jnr.22054","article-title":"Stem cell-based cell therapy in neurological diseases: A review","volume":"87","author":"Kim","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"181","DOI":"10.46582\/jsrm.0803011","article-title":"Autologous intravenous mononuclear stem cell therapy in chronic ischemic stroke","volume":"8","author":"Bhasin","year":"2012","journal-title":"J. Stem Cells Regen. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3727\/096368913X675755","article-title":"Long-term effects of magnetically targeted ferumoxide-labeled human neural stem cells in focal cerebral ischemia","volume":"24","author":"Song","year":"2015","journal-title":"Cell Transplant."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1634\/stemcells.2004-0122","article-title":"Derivation and characterization of new human embryonic stem cell lines: SNUhES1, SNUhES2, and SNUhES3","volume":"23","author":"Oh","year":"2005","journal-title":"Stem Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1038\/nbt1201-1129","article-title":"In vitro differentiation of transplantable neural precursors from human embryonic stem cells","volume":"19","author":"Zhang","year":"2001","journal-title":"Nat. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1038\/nprot.2008.188","article-title":"Efficient derivation of functional dopaminergic neurons from human embryonic stem cells on a large scale","volume":"3","author":"Cho","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1073\/pnas.1016409108","article-title":"Magnetosome-like ferrimagnetic iron oxide nanocubes for highly sensitive MRI of single cells and transplanted pancreatic islets","volume":"108","author":"Lee","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8733","DOI":"10.1038\/srep08733","article-title":"Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways","volume":"5","author":"Gu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13287-015-0015-3","article-title":"Stem cells labeled with superparamagnetic iron oxide nanoparticles in a preclinical model of cerebral ischemia: A systematic review with meta-analysis","volume":"6","author":"Nucci","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1016\/j.biomaterials.2012.11.040","article-title":"Superparamagnetic iron oxide nanoparticle targeting of MSCs in vascular injury","volume":"34","author":"Riegler","year":"2013","journal-title":"Biomaterials"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1384658","DOI":"10.1155\/2016\/1384658","article-title":"Nanoparticles-assisted stem cell therapy for ischemic heart disease","volume":"2016","author":"Zhu","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/01.rli.0000197669.80475.dd","article-title":"Preclinical safety and pharmacokinetic profile of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent","volume":"41","author":"Bourrinet","year":"2006","journal-title":"Investig. Radiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Meng, Y., Shi, C., Hu, B., Gong, J., Zhong, X., Lin, X., Zhang, X., Liu, J., Liu, C., and Xu, H. (2017). External magnetic field promotes homing of magnetized stem cells following subcutaneous injection. BMC Cell Biol., 18.","DOI":"10.1186\/s12860-017-0140-1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29","DOI":"10.5853\/jos.2019.02236","article-title":"Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets","volume":"22","author":"Tschoe","year":"2020","journal-title":"J. Stroke"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1161\/STROKEAHA.118.024403","article-title":"Determinants of early versus delayed neurological deterioration in intracerebral hemorrhage","volume":"50","author":"You","year":"2019","journal-title":"Stroke"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.brainres.2007.08.058","article-title":"Evolution of the inflammatory response in the brain following intracerebral hemorrhage and effects of delayed minocycline treatment","volume":"1180","author":"Wasserman","year":"2007","journal-title":"Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1097\/00075198-200404000-00003","article-title":"Novel therapies for intracerebral hemorrhage","volume":"10","author":"Rincon","year":"2004","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.1002\/dvdy.21306","article-title":"Directing the differentiation of embryonic stem cells to neural stem cells","volume":"236","author":"Cai","year":"2007","journal-title":"Dev. Dyn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1385\/MN:34:3:153","article-title":"Strengths and limitations of the neurosphere culture system","volume":"34","author":"Jensen","year":"2006","journal-title":"Mol. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4849","DOI":"10.2147\/IJN.S204910","article-title":"Strategies to enhance efficacy of SPION-labeled stem cell homing by magnetic attraction: A systemic review with meta-analysis","volume":"14","author":"Ahn","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1089\/hum.2009.144","article-title":"Using a neodymium magnet to target delivery of ferumoxide-labeled human neural stem cells in a rat model of focal cerebral ischemia","volume":"21","author":"Song","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_32","first-page":"45","article-title":"Static magnetic field enhances the viability and proliferation rate of adipose tissue-derived mesenchymal stem cells potentially through activation of the phosphoinositide 3-kinase\/Akt (PI3K\/Akt) pathway","volume":"36","author":"Maredziak","year":"2017","journal-title":"Electromagn. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.2147\/IJN.S128525","article-title":"Lipid-coated iron oxide nanoparticles for dual-modal imaging of hepatocellular carcinoma","volume":"12","author":"Liang","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/978-1-61779-201-4_15","article-title":"Immunocytochemical analysis of human pluripotent stem cells","volume":"767","author":"Nethercott","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.expneurol.2018.08.013","article-title":"Pretreatment with low-dose fimasartan ameliorates NLRP3 inflammasome-mediated neuroinflammation and brain injury after intracerebral hemorrhage","volume":"310","author":"Yang","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_36","first-page":"1","article-title":"Effect of elevation of vascular endothelial growth factor level on exacerbation of hemorrhage in mouse brain arteriovenous malformation","volume":"1","author":"Cheng","year":"2019","journal-title":"J. Neurosurg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1179\/1743132812Y.0000000015","article-title":"Lithium pretreatment reduces brain injury after intracerebral hemorrhage in rats","volume":"34","author":"Kang","year":"2012","journal-title":"Neurol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1161\/01.STR.0000088060.83709.2C","article-title":"Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage","volume":"34","author":"Song","year":"2003","journal-title":"Stroke"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1658195","DOI":"10.1155\/2018\/1658195","article-title":"Human placenta-derived mesenchymal stem cells reduce mortality and hematoma size in a rat intracerebral hemorrhage model in an acute phase","volume":"2018","author":"Choi","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"943","DOI":"10.3346\/jkms.2015.30.7.943","article-title":"Agmatine attenuates brain edema and apoptotic cell death after traumatic brain injury","volume":"30","author":"Kim","year":"2015","journal-title":"J. Korean Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/jcbfm.2013.35","article-title":"Detrimental effects of leptin on intracerebral hemorrhage via the STAT3 signal pathway","volume":"33","author":"Kim","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.eplepsyres.2011.01.002","article-title":"Different effects of high- and low-dose phenobarbital on post-stroke seizure suppression and recovery in immature CD1 mice","volume":"94","author":"Markowitz","year":"2011","journal-title":"Epilepsy Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3658\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:31:26Z","timestamp":1760175086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3658"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,22]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21103658"],"URL":"https:\/\/doi.org\/10.3390\/ijms21103658","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,22]]}}}