{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T15:17:34Z","timestamp":1782832654491,"version":"3.54.5"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 108-2314-B-075 -015"],"award-info":[{"award-number":["MOST 108-2314-B-075 -015"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taipei Veterans General Hospital, Taipei","award":["V110C-023"],"award-info":[{"award-number":["V110C-023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Stroke is a leading cause of adult disability. In our previous study, transplantation of human umbilical mesenchymal stem cells (HUMSCs) in Wharton\u2019s jelly in the acute phase of ischemic stroke promotes recovery in rats. Unfortunately, there is no cure for chronic stroke. Patients with chronic stroke can only be treated with rehabilitation or supportive interventions. This study aimed to investigate the potential of xenograft of HUMSCs for treating chronic stroke in rats. Rats were subjected to 90 min middle cerebral artery occlusion and then reperfusion to mimic ischemic cerebral stroke. On day 14 following stroke, HUMSCs were transplanted into the damaged cerebral cortex. The motor function in rats of the Stroke + HUMSCs group exhibited significant improvement compared to that of the Stroke + Saline group, and the trend persisted until day 56 post stroke. The cerebral cortex changes were tracked using magnetic resonance imaging, showing that cerebral atrophy was found starting on day 7 and was reduced significantly in rats receiving HUMSCs compared to that in the Stroke + Saline group from day 21 to day 56. HUMSCs were found to be existed in the rats\u2019 cerebral cortex on day 56, with signs of migration. The grafted HUMSCs did not differentiate into neurons or astrocytes and may release cytokines to improve neuroprotection, decrease inflammation and increase angiogenesis. Our results demonstrate that xeno-transplantation of HUMSCs has therapeutic benefits for chronic ischemic stroke. Most importantly, patients do not need to use their own HUMSCs, which is a gospel thing for clinical patients.<\/jats:p>","DOI":"10.3390\/ijms23063149","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T03:34:13Z","timestamp":1647401653000},"page":"3149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Xenograft of Human Umbilical Mesenchymal Stem Cells Promotes Recovery from Chronic Ischemic Stroke in Rats"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4754-6006","authenticated-orcid":false,"given":"Yu-Show","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0690-7503","authenticated-orcid":false,"given":"Chang-Ching","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Department of Obstetrics and Gynecology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Department of Nurse-Midwifery and Women Health, National Taipei University of Nursing and Health Sciences, Taipei 112303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Ming","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, China Medical University, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hsing","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maan-Yuh Anya","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Department of Pharmacy, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Yang","family":"Lin","sequence":"additional","affiliation":[{"name":"Neurological Institute, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1161\/CIR.0000000000000485","article-title":"Heart disease and stroke statistics-2017 update: A report from the American Heart Association","volume":"135","author":"Benjamin","year":"2017","journal-title":"Circulation"},{"key":"ref_2","unstructured":"World Health Organization (2020, December 09). The Top 10 Causes of Death. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/the-top-10-causes-of-death."},{"key":"ref_3","first-page":"e46","article-title":"Heart disease and stroke statistics\u20142010 update: A report from the American Heart Association","volume":"121","author":"Members","year":"2010","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kowalska, K., Krzywosza\u0144ski, \u0141., Dro\u015b, J., Pasi\u0144ska, P., Wilk, A., and Klimkowicz-Mrowiec, A. (2020). Early Depression Independently of Other Neuropsychiatric Conditions, Influences Disability and Mortality after Stroke (Research Study-Part of PROPOLIS Study). Biomedicines, 8.","DOI":"10.3390\/biomedicines8110509"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1177\/1545968320953671","article-title":"Serum Kynurenines Correlate with Depressive Symptoms and Disability in Poststroke Patients: A Cross-sectional Study","volume":"34","year":"2020","journal-title":"Neurorehabilt. Neural Repair"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tanaka, M., and V\u00e9csei, L. (2021). Editorial of Special Issue \u201cCrosstalk between Depression, Anxiety, and Dementia: Comorbidity in Behavioral Neurology and Neuropsychiatry\u201d. Biomedicines, 9.","DOI":"10.3390\/biomedicines9050517"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Nishimura, K., and Takata, K. (2021). Combination of Drugs and Cell Transplantation: More Beneficial Stem Cell-Based Regenerative Therapies Targeting Neurological Disorders. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22169047"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Suda, S., Nito, C., Yokobori, S., Sakamoto, Y., Nakajima, M., Sowa, K., Obinata, H., Sasaki, K., Savitz, S.I., and Kimura, K. (2020). Recent advances in cell-based therapies for ischemic stroke. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186718"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1634\/stemcells.2005-0053","article-title":"Conversion of human umbilical cord mesenchymal stem cells in Wharton\u2019s jelly to dopaminergic neurons in vitro: Potential therapeutic application for Parkinsonism","volume":"24","author":"Fu","year":"2006","journal-title":"Stem Cells"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.3727\/096368914X685078","article-title":"A high-efficiency induction of dopaminergic cells from human umbilical mesenchymal stem cells for the treatment of hemiparkinsonian rats","volume":"24","author":"Ko","year":"2015","journal-title":"Cell Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yang, C.C., Shih, Y.H., Ko, M.H., Hsu, S.Y., Cheng, H., and Fu, Y.S. (2008). Transplantation of human umbilical mesenchymal stem cells from Wharton\u2019s jelly after complete transection of the rat spinal cord. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003336"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1161\/STROKEAHA.110.603621","article-title":"Human umbilical mesenchymal stem cells promote recovery after ischemic stroke","volume":"42","author":"Lin","year":"2011","journal-title":"Stroke"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.bbi.2015.12.021","article-title":"Xenograft of human umbilical mesenchymal stem cells from Wharton\u2019s jelly as a potential therapy for rat pilocarpine-induced epilepsy","volume":"54","author":"Huang","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40035-019-0166-8","article-title":"Xenografting of human umbilical mesenchymal stem cells from Wharton\u2019s jelly ameliorates mouse spinocerebellar ataxia type 1","volume":"8","author":"Tsai","year":"2019","journal-title":"Transl. Neurodegener."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/lt.21715","article-title":"The therapeutic potential of human umbilical mesenchymal stem cells from Wharton\u2019s jelly in the treatment of rat liver fibrosis","volume":"15","author":"Tsai","year":"2009","journal-title":"Liver Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"235","DOI":"10.5966\/sctm.2015-0001","article-title":"The Therapeutic Potential of Human Umbilical Mesenchymal Stem Cells from Wharton\u2019s Jelly in the Treatment of Rat Peritoneal Dialysis-Induced Fibrosis","volume":"5","author":"Fan","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6646","DOI":"10.7150\/thno.33741","article-title":"Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton\u2019s jelly","volume":"9","author":"Chu","year":"2019","journal-title":"Theranostics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1186\/s13287-020-02012-y","article-title":"Comparison of reversal of rat pulmonary fibrosis of nintedanib, pirfenidone, and human umbilical mesenchymal stem cells from Wharton\u2019s jelly","volume":"11","author":"Chu","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chao, K.C., Chao, K.F., Fu, Y.S., and Liu, S.H. (2008). Islet-like clusters derived from mesenchymal stem cells in Wharton\u2019s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001451"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1177\/0963689717750666","article-title":"Xenograft of human umbilical mesenchymal stem cells from Wharton\u2019s jelly differentiating into osteocytes and reducing osteoclast activity reverses osteoporosis in ovariectomized rats","volume":"27","author":"Fu","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chen, C.F., Chen, Y.C., Fu, Y.S., Tsai, S.W., Wu, P.K., Chen, C.M., Chang, M.C., and Chen, W.M. (2021). Characterization of Osteogenesis and Chondrogenesis of Human Decellularized Allogeneic Bone with Mesenchymal Stem Cells Derived from Bone Marrow, Adipose Tissue, and Wharton\u2019s Jelly. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168987"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.brainres.2009.09.094","article-title":"Therapeutic window for treatment of cortical ischemia with bone marrow-derived cells in rats","volume":"1306","author":"Paredes","year":"2010","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/jcbfm.2010.81","article-title":"Cell number and timing of transplantation determine survival of human neural stem cell grafts in stroke-damaged rat brain","volume":"31","author":"Darsalia","year":"2011","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1161\/STROKEAHA.112.677328","article-title":"Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke","volume":"44","author":"Ishizaka","year":"2013","journal-title":"Stroke"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/jcbfm.2013.32","article-title":"Cell size and velocity of injection are major determinants of the safety of intracarotid stem cell transplantation","volume":"33","author":"Janowski","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1007\/s12975-016-0482-6","article-title":"Stem Cell Therapy and Administration Routes After Stroke","volume":"7","author":"Fuentes","year":"2016","journal-title":"Transl. Stroke Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1161\/STROKEAHA.110.593129","article-title":"Delayed administration of human umbilical tissue-derived cells improved neurological functional recovery in a rodent model of focal ischemia","volume":"42","author":"Zhang","year":"2011","journal-title":"Stroke"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hamblin, M.H., and Lee, J.P. (2021). Neural Stem Cells for Early Ischemic Stroke. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147703"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"32291","DOI":"10.1038\/srep32291","article-title":"Meta-Analysis and Systematic Review of Neural Stem Cells therapy for experimental ischemia stroke in preclinical studies","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12974-018-1153-1","article-title":"Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice","volume":"15","author":"Cheng","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1080\/02699052.2021.1906948","article-title":"Contribution of Human Trophoblast Progenitor Cells to Neurogenesis in Rat Focal Cerebral Ischemia Model","volume":"35","author":"Yanar","year":"2021","journal-title":"Brain Inj."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"558","DOI":"10.7150\/ijbs.11051","article-title":"Direct Reprogramming of Human Amniotic Fluid Stem Cells by OCT4 and Application in Repairing of Cerebral Ischemia Damage","volume":"12","author":"Qin","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/156720211794520215","article-title":"Transplantation of adipose tissue-derived stem cells for treatment of focal cerebral ischemia","volume":"8","author":"Yang","year":"2011","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1002\/sctm.17-0074","article-title":"Long-Term Recovery After Endothelial Colony-Forming Cells or Human Umbilical Cord Blood Cells Administration in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy","volume":"6","author":"Grandvuillemin","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1177\/0963689718795424","article-title":"Transplanting Mesenchymal Stem Cells for Treatment of Ischemic Stroke","volume":"27","author":"Wang","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/nm747","article-title":"Neuronal replacement from endogenous precursors in the adult brain after stroke","volume":"8","author":"Arvidsson","year":"2002","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s13287-018-0913-2","article-title":"Neural stem cell therapy for subacute and chronic ischemic stroke","volume":"9","author":"Boese","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1002\/ana.10393","article-title":"Rat forebrain neurogenesis and striatal neuron replacement after focal stroke","volume":"52","author":"Parent","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1016\/j.jstrokecerebrovasdis.2014.05.032","article-title":"Anti-inflammatory and antiapoptotic effects of mesenchymal stem cells transplantation in rat brain with cerebral ischemia","volume":"23","author":"Gu","year":"2014","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s12264-019-00405-5","article-title":"Neural Stem Cells Transfected with Leukemia Inhibitory Factor Promote Neuroprotection in a Rat Model of Cerebral Ischemia","volume":"35","author":"Tian","year":"2019","journal-title":"Neurosci. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e2774","DOI":"10.1038\/cddis.2017.184","article-title":"Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co-overexpressing BDNF and VEGF in a rat model of cardiac arrest-induced global cerebral ischemia","volume":"8","author":"Zhou","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"111709","DOI":"10.1016\/j.biopha.2021.111709","article-title":"Enhancement of angiogenesis and neurogenesis by intracerebroventricular injection of secretome from human embryonic stem cell-derived mesenchymal stem cells in ischemic stroke model","volume":"140","author":"Nasoohi","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1089\/scd.2018.0254","article-title":"Enhanced Migration of Bone Marrow-Derived Mesenchymal Stem Cells with Tetramethylpyrazine and Its Synergistic Effect on Angiogenesis and Neurogenesis After Cerebral Ischemia in Rats","volume":"28","author":"Li","year":"2019","journal-title":"Stem Cells Dev."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Moon, S., Chang, M.S., Koh, S.H., and Choi, Y.K. (2021). Repair Mechanisms of the Neurovascular Unit after Ischemic Stroke with a Focus on VEGF. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168543"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1177\/0271678X18766172","article-title":"Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke","volume":"39","author":"Neal","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S1474-4422(19)30078-X","article-title":"Global brain inflammation in stroke","volume":"18","author":"Shi","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7370","DOI":"10.1021\/acsnano.1c00672","article-title":"Embryonic Stem Cell Derived Small Extracellular Vesicles Modulate Regulatory T Cells to Protect against Ischemic Stroke","volume":"15","author":"Xia","year":"2021","journal-title":"ACS Nano"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1186\/s12967-018-1709-y","article-title":"Immunological effects of the intraparenchymal administration of allogeneic and autologous adipose-derived mesenchymal stem cells after the acute phase of middle cerebral artery occlusion in rats","volume":"16","author":"Yu","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12967-015-0406-3","article-title":"Comparison between xenogeneic and allogeneic adipose mesenchymal stem cells in the treatment of acute cerebral infarct: Proof of concept in rats","volume":"13","author":"Fuentes","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1161\/CIRCRESAHA.116.304872","article-title":"Similar effect of autologous and allogeneic cell therapy for ischemic heart disease: Systematic review and meta-analysis of large animal studies","volume":"116","author":"Eding","year":"2015","journal-title":"Circ. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3149\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:36:47Z","timestamp":1760135807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3149"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,15]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23063149"],"URL":"https:\/\/doi.org\/10.3390\/ijms23063149","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,15]]}}}