{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:03:56Z","timestamp":1782536636641,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005492","name":"Stanford University","doi-asserted-by":"publisher","award":["SINTN"],"award-info":[{"award-number":["SINTN"]}],"id":[{"id":"10.13039\/100005492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005492","name":"Stanford University","doi-asserted-by":"publisher","award":["125100"],"award-info":[{"award-number":["125100"]}],"id":[{"id":"10.13039\/100005492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ohio State University","award":["SINTN"],"award-info":[{"award-number":["SINTN"]}]},{"name":"Ohio State University","award":["125100"],"award-info":[{"award-number":["125100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter, and improving forelimb function after a spinal cord injury (SCI). We proposed that by preconditioning the mouse by the intravenous delivery (IV) of MPCs for 24 h following SCI, this would provide a more favorable tissue milieu for an NSC intraspinal bridging transplantation at day three and day seven. In combination, these transplants will provide better anatomical and functional outcomes. The intravenous MSCs would provide cell protection and reduce inflammation. NSCs would provide a tissue bridge for axonal regeneration and myelination and reconnect long tract spinal pathways. Results showed that initial protection of the injury site by IV MPCs transplantation resulted in no increased survival of the NSCs transplanted at day seven. However, integration of transplanted NSCs was increased at the day three timepoint, indicating MPCs influence very early immune signaling. We show, in this study, that MPC transplantation resulted in a co-operative NSC cell survival improvement on day three post-SCI. In addition to increased NSC survival on day three, there was an increase in NSC-derived mature oligodendrocytes at this early timepoint. An in vitro analysis confirmed MPC-driven oligodendrocyte differentiation, which was statistically increased when compared to control NSC-only cultures. These observations provide important information about the combination, delivery, and timing of two cellular therapies in treating SCI. This study provides important new data on understanding the MPC inflammatory signaling within the host tissue and timepoints for cellular transplantation survival and oligodendroglia differentiation. These results demonstrate that MPC transplantation can alter the therapeutic window for intraspinal transplantation by controlling both the circulating inflammatory response and local tissue milieu.<\/jats:p>","DOI":"10.3390\/cells14090630","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T06:38:37Z","timestamp":1745390317000},"page":"630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Combined Transplantation of Mesenchymal Progenitor and Neural Stem Cells to Repair Cervical Spinal Cord Injury"],"prefix":"10.3390","volume":"14","author":[{"given":"Seok Voon","family":"White","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"name":"School of Human Sciences, University of Western Australia, Crawley, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0537-8896","authenticated-orcid":false,"given":"Yee Hang Ethan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine D.","family":"Plant","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Harvey","sequence":"additional","affiliation":[{"name":"School of Human Sciences, University of Western Australia, Crawley, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7366-652X","authenticated-orcid":false,"given":"Giles W.","family":"Plant","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA"},{"name":"Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA"},{"name":"Chronic Brain Injury Program, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1089\/neu.2006.23.468","article-title":"Olfactory ensheathing cells: Characteristics, genetic engineering, and therapeutic potential","volume":"23","author":"Ruitenberg","year":"2006","journal-title":"J. Neurotrauma"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1089\/neu.2009.1177","article-title":"A systematic review of cellular transplantation therapies for spinal cord injury","volume":"28","author":"Tetzlaff","year":"2011","journal-title":"J. Neurotrauma"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3727\/096368912X655208","article-title":"Systematic review of induced pluripotent stem cell technology as a potential clinical therapy for spinal cord injury","volume":"22","author":"Kramer","year":"2013","journal-title":"Cell Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Silver, J., Schwab, M.E., and Popovich, P.G. (2015). Central nervous system regenerative failure: Role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol., 7.","DOI":"10.1101\/cshperspect.a020602"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1016\/j.biochi.2013.08.004","article-title":"The role of mesenchymal stromal cells in spinal cord injury, regenerative medicine and possible clinical applications","volume":"95","author":"Forostyak","year":"2013","journal-title":"Biochimie"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"120","DOI":"10.4252\/wjsc.v6.i2.120","article-title":"Mesenchymal stem cells in the treatment of spinal cord injuries: A review","volume":"6","author":"Dasari","year":"2014","journal-title":"World J. Stem Cells"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3727\/096368912X656081","article-title":"Human mesenchymal precursor cells (Stro-1(+)) from spinal cord injury patients improve functional recovery and tissue sparing in an acute spinal cord injury rat model","volume":"22","author":"Hodgetts","year":"2013","journal-title":"Cell Transplant."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7599","DOI":"10.1523\/JNEUROSCI.16-23-07599.1996","article-title":"Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis","volume":"16","author":"Weiss","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.5966\/sctm.2014-0029","article-title":"Neural precursor cell transplantation enhances functional recovery and reduces astrogliosis in bilateral compressive\/contusive cervical spinal cord injury","volume":"3","author":"Wilcox","year":"2014","journal-title":"Stem Cells Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.brainres.2015.01.006","article-title":"Repair of spinal cord injury with neuronal relays: From fetal grafts to neural stem cells","volume":"1619","author":"Bonner","year":"2015","journal-title":"Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1002\/glia.22851","article-title":"Endogenous neural stem cell responses to stroke and spinal cord injury","volume":"63","author":"Goldenstein","year":"2015","journal-title":"Glia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.scr.2015.07.001","article-title":"Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury","volume":"15","author":"Piltti","year":"2015","journal-title":"Stem Cell Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1089\/scd.2014.0096","article-title":"Transplantation of neural stem cells clonally derived from embryonic stem cells promotes recovery after murine spinal cord injury","volume":"24","author":"Salewski","year":"2015","journal-title":"Stem Cells Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1001\/jamaneurol.2014.2927","article-title":"Role of endogenous neural stem cells in spinal cord injury and repair","volume":"72","author":"Stenudd","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/jnr.22288","article-title":"Promoting directional axon growth from neural progenitors grafted into the injured spinal cord","volume":"88","author":"Bonner","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/08977150360517146","article-title":"Delayed transplantation of olfactory ensheathing glia promotes sparing\/regeneration of supraspinal axons in the contused adult rat spinal cord","volume":"20","author":"Plant","year":"2003","journal-title":"J. Neurotrauma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14069","DOI":"10.1073\/pnas.0507063102","article-title":"Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice","volume":"102","author":"Cummings","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","unstructured":"Lee, S.V., Czisch, C.E., Huang, Y., Han, M.H., Harvey, A.R., and Plant, G.W. (2014, January 15). Early intravenous delivery of mesenchymal progenitor cells leads to behavioral and pathological amelioration after cervical spinal cord injury. Proceedings of the Society for Neuroscience 44th Annual Meeting: Abstract No. 4812, Washington, DC, USA."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1002\/stem.2364","article-title":"Intravenous Transplantation of Mesenchymal Progenitors Distribute Solely to the Lungs and Improve Outcomes in Cervical Spinal Cord Injury","volume":"34","author":"White","year":"2016","journal-title":"Stem Cells"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3727\/096368910X539083","article-title":"Cotransplantation of mouse neural stem cells (mNSCs) with adipose tissue-derived mesenchymal stem cells improves mNSC survival in a rat spinal cord injury model","volume":"20","author":"Oh","year":"2011","journal-title":"Cell Transplant."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/978-1-59745-060-7_16","article-title":"Prospective isolation of mesenchymal stem cells from mouse compact bone","volume":"482","author":"Short","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/(SICI)1096-9861(19970120)377:3<443::AID-CNE10>3.0.CO;2-S","article-title":"Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats","volume":"377","author":"Popovich","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1073\/pnas.2637010100","article-title":"Shifting foci of hematopoiesis during reconstitution from single stem cells","volume":"101","author":"Cao","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jcmg.2011.07.011","article-title":"Molecular imaging of bone marrow mononuclear cell survival and homing in murine peripheral artery disease","volume":"5","author":"Hellingman","year":"2012","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Azari, H., Rahman, M., Sharififar, S., and Reynolds, B.A. (2010). Isolation and expansion of the adult mouse neural stem cells using the neurosphere assay. J. Vis. Exp.","DOI":"10.3791\/2393-v"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S0028-3908(00)00005-8","article-title":"CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury","volume":"39","author":"Schallert","year":"2000","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1006\/mcne.2000.0948","article-title":"Inhibitory proteoglycan immunoreactivity is higher at the caudal than the rostral Schwann cell graft-transected spinal cord interface","volume":"17","author":"Plant","year":"2001","journal-title":"Mol. Cell Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lankford, K.L., Arroyo, E.J., Nazimek, K., Bryniarski, K., Askenase, P.W., and Kocsis, J.D. (2018). Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0190358"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nakazaki, M., Morita, T., Lankford, K.L., Askenase, P.W., and Kocsis, J.D. (2021). Small extracellular vesicles released by infused mesenchymal stromal cells target M2 macrophages and promote TGF-\u03b2 upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injury. J. Extracell. Vesicles, 10.","DOI":"10.1002\/jev2.12137"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1002\/(SICI)1097-4547(19960901)45:5<588::AID-JNR8>3.0.CO;2-8","article-title":"Effects of Schwann cell transplantation in a contusion model of rat spinal cord injury","volume":"45","author":"Martin","year":"1996","journal-title":"J. Neurosci. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Barbour, H.R., Plant, C.D., Harvey, A.R., and Plant, G.W. (2013). Tissue sparing, behavioral recovery, supraspinal axonal sparing\/regeneration following sub-acute glial transplantation in a model of spinal cord contusion. BMC Neurosci., 14.","DOI":"10.1186\/1471-2202-14-106"},{"key":"ref_32","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_33","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1073\/pnas.0501029102","article-title":"Adult human hematopoietic stem cells produce neurons efficiently in the regenerating chicken embryo spinal cord","volume":"102","author":"Sigurjonsson","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7435","DOI":"10.1016\/j.biomaterials.2012.06.085","article-title":"Neo-vascularization of the stroke cavity by implantation of human neural stem cells on VEGF-releasing PLGA microparticles","volume":"33","author":"Bible","year":"2012","journal-title":"Biomaterials"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/j.cell.2012.08.020","article-title":"Long-distance growth and connectivity of neural stem cells after severe spinal cord injury","volume":"150","author":"Lu","year":"2012","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1016\/j.biomaterials.2012.10.070","article-title":"Templated agarose scaffolds for the support of motor axon regeneration into sites of complete spinal cord transection","volume":"34","author":"Gao","year":"2013","journal-title":"Biomaterials"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1006\/exnr.2002.7981","article-title":"Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord","volume":"177","author":"Cao","year":"2002","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.stemcr.2014.03.005","article-title":"Injury to the spinal cord niche alters the engraftment dynamics of human neural stem cells","volume":"2","author":"Sontag","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_39","first-page":"4268","article-title":"Incorporation and differentiation of hippocampus-derived neural stem cells transplanted in injured adult rat retina","volume":"41","author":"Nishida","year":"2000","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ma, Y.H.E., Putta, A.R., Chan, C.H.H., Vidman, S.R., Monje, P., and Plant, G.W. (2025). Efficacy of Deferoxamine Mesylate in Serum and Serum-Free Media: Adult Ventral Root Schwann Cell Survival Following Hydrogen Peroxide-Induced Cell Death. Cells, 14.","DOI":"10.1101\/2025.01.23.634338"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8727","DOI":"10.1523\/JNEUROSCI.20-23-08727.2000","article-title":"Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus","volume":"20","author":"Shihabuddin","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Suh, H., Zhou, Q.-G., Fernandez-Carasa, I., Clemenson, G.D., Pons-Espinal, M., Ro, E.J., Marti, M., Raya, A., Gage, F.H., and Consiglio, A. (2018). Long-Term Labeling of Hippocampal Neural Stem Cells by a Lentiviral Vector. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00415"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lu, P., Graham, L., Wang, Y., Wu, D., and Tuszynski, M. (2014). Promotion of survival and differentiation of neural stem cells with fibrin and growth factor cocktails after severe spinal cord injury. J. Vis. Exp.","DOI":"10.3791\/50641"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.actbio.2015.09.018","article-title":"Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury","volume":"28","author":"Wilems","year":"2015","journal-title":"Acta Biomater."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/9\/630\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:20:00Z","timestamp":1760030400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/9\/630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,23]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["cells14090630"],"URL":"https:\/\/doi.org\/10.3390\/cells14090630","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.02.13.638141","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,23]]}}}