{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:13:28Z","timestamp":1791558808366,"version":"4.3.4"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Fondazione Revert Onlus","award":["Fondazione Revert Onlus"],"award-info":[{"award-number":["Fondazione Revert Onlus"]}]},{"DOI":"10.13039\/501100002954","name":"Universit\u00e0 degli Studi di Milano-Bicocca","doi-asserted-by":"publisher","award":["2019-ATESP-0028"],"award-info":[{"award-number":["2019-ATESP-0028"]}],"id":[{"id":"10.13039\/501100002954","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["Dipartimenti di Eccellenza 2023-2027 to Department of Neuroscience \"Rita Levi Montalcini\""],"award-info":[{"award-number":["Dipartimenti di Eccellenza 2023-2027 to Department of Neuroscience \"Rita Levi Montalcini\""]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["R24-5x1000 to Fondazione IRCCS Casa Sollievo della Sofferenza"],"award-info":[{"award-number":["R24-5x1000 to Fondazione IRCCS Casa Sollievo della Sofferenza"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Neural stem cell (NSC) transplantation holds promising therapeutic potential for neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). However, pre-clinical studies and early-phase clinical trials have faced challenges hindering the effective clinical translation of this approach. Crucial hurdles include the side-effects of prolonged immunosuppression, concerns regarding cell origin and transplantation dosage, identification of the most appropriate therapeutic window, and invasiveness of surgical procedures. Here, we assessed the safety and efficacy of intracerebroventricular (ICV) hNSC transplantation as a novel and possibly more effective experimental approach for ALS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We evaluated the safety of administering up to 1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> hNSCs in immunodeficient mice and assessed their potential efficacy in reducing ALS hallmarks employing the SOD1<jats:sup>G93A<\/jats:sup> mouse model. Both transient (15 days) and prolonged immunosuppression regimens, at low (15\u00a0mg\/kg) and high (30\u00a0mg\/kg) doses, were tested along with two different cell dosages (3\u2009\u00d7\u200910<jats:sup>5<\/jats:sup> and 1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup>).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Our study suggests that: (i) a bilateral ICV transplantation of 1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> hNSCs is safe and non-tumorigenic in immunodeficient hosts; (ii) sustained and high-dose immunosuppression is essential for ensuring cell survival in immunocompetent SOD1<jats:sup>G93A<\/jats:sup> mice; and (iii) hNSCs may delay motor symptom progression and reduce spinal cord microgliosis in SOD1<jats:sup>G93A<\/jats:sup> mice when administered in the lateral ventricles under prolonged high-dose (30\u00a0mg\/kg) immunosuppression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>ICV transplantation of hNSCs emerges as a safe and promising strategy for ALS, demonstrating potential to delay motor decline and reduce spinal cord microgliosis. However, sustained high-dose immunosuppression is crucial for therapeutic efficacy, emphasizing the need for further optimization to overcome translational challenges and achieve durable clinical benefits.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12967-025-06529-9","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T14:35:26Z","timestamp":1746801326000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Safety and efficacy evaluation of intracerebroventricular human neural stem cell transplantation in SOD1 mice as a novel approach for ALS"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5682-0823","authenticated-orcid":false,"given":"Ivan","family":"Lombardi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clelia","family":"Ferrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4550-3907","authenticated-orcid":false,"given":"Edvige","family":"Vulcano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Maria","family":"Ras\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Gelati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Pastor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose Mary","family":"Carletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"de la Morena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Celeste","family":"Profico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Longobardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Lazzarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Perciballi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Diana","family":"Rosati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Vercelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo Luigi","family":"Vescovi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1211-1552","authenticated-orcid":false,"given":"Marina","family":"Boido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7251-9854","authenticated-orcid":false,"given":"Daniela","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"issue":"2","key":"6529_CR1","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJMra1603471","volume":"377","author":"RH Brown","year":"2017","unstructured":"Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162\u201372.","journal-title":"N Engl J Med"},{"issue":"5","key":"6529_CR2","doi-asserted-by":"publisher","first-page":"a024125","DOI":"10.1101\/cshperspect.a024125","volume":"8","author":"M Ghasemi","year":"2018","unstructured":"Ghasemi M, Brown RH. Genetics of amyotrophic lateral sclerosis. Cold Spring Harb Perspect Med. 2018;8(5):a024125.","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"4","key":"6529_CR3","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.ncl.2015.07.001","volume":"33","author":"K Boylan","year":"2015","unstructured":"Boylan K. Familial amyotrophic lateral sclerosis. Neurol Clin. 2015;33(4):807\u201330.","journal-title":"Neurol Clin"},{"issue":"7628","key":"6529_CR4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nature20413","volume":"539","author":"JP Taylor","year":"2016","unstructured":"Taylor JP, Brown RH, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539(7628):197\u2013206.","journal-title":"Nature"},{"issue":"1","key":"6529_CR5","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s40035-021-00250-5","volume":"10","author":"X Xu","year":"2021","unstructured":"Xu X, Shen D, Gao Y, Zhou Q, Ni Y, Meng H, et al. A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed? Transl Neurodegener. 2021;10(1):29.","journal-title":"Transl Neurodegener"},{"issue":"8","key":"6529_CR6","doi-asserted-by":"publisher","first-page":"3783","DOI":"10.1007\/s10571-023-01423-8","volume":"43","author":"L Zhou","year":"2023","unstructured":"Zhou L, Chen W, Jiang S, Xu R. Vitro models of amyotrophic lateral sclerosis. Cell Mol Neurobiol. 2023;43(8):3783\u201399.","journal-title":"Cell Mol Neurobiol"},{"issue":"1","key":"6529_CR7","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s40035-023-00377-7","volume":"12","author":"L Zhu","year":"2023","unstructured":"Zhu L, Li S, Li XJ, Yin P. Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges. Transl Neurodegener. 2023;12(1):46.","journal-title":"Transl Neurodegener"},{"key":"6529_CR8","doi-asserted-by":"publisher","first-page":"146615","DOI":"10.1016\/j.brainres.2019.146615","volume":"1729","author":"CM Willis","year":"2020","unstructured":"Willis CM, Nicaise AM, Peruzzotti-Jametti L, Pluchino S. The neural stem cell secretome and its role in brain repair. Brain Res. 2020;1729:146615.","journal-title":"Brain Res"},{"key":"6529_CR9","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1093\/bmb\/lds024","volume":"104","author":"G Gincberg","year":"2012","unstructured":"Gincberg G, Arien-Zakay H, Lazarovici P, Lelkes PI. Neural stem cells: therapeutic potential for neurodegenerative diseases. Br Med Bull. 2012;104:7\u201319.","journal-title":"Br Med Bull"},{"key":"6529_CR10","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.brainresbull.2023.01.008","volume":"194","author":"F Sironi","year":"2023","unstructured":"Sironi F, De Marchi F, Mazzini L, Bendotti C. Cell therapy in ALS: an update on preclinical and clinical studies. Brain Res Bull. 2023;194:64\u201381.","journal-title":"Brain Res Bull"},{"issue":"4","key":"6529_CR11","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1212\/WNL.0000000000002889","volume":"87","author":"JD Glass","year":"2016","unstructured":"Glass JD, Hertzberg VS, Boulis NM, Riley J, Federici T, Polak M, et al. Transplantation of spinal cord-derived neural stem cells for ALS: analysis of phase 1 and 2 trials. Neurology. 2016;87(4):392\u2013400.","journal-title":"Neurology"},{"issue":"5","key":"6529_CR12","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/s41419-019-1582-5","volume":"10","author":"C Zalfa","year":"2019","unstructured":"Zalfa C, Rota Nodari L, Vacchi E, Gelati M, Profico D, Boido M, et al. Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats. Cell Death Dis. 2019;10(5):345.","journal-title":"Cell Death Dis"},{"issue":"3","key":"6529_CR13","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1002\/ana.24113","volume":"75","author":"EL Feldman","year":"2014","unstructured":"Feldman EL, Boulis NM, Hur J, Johe K, Rutkove SB, Federici T, et al. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol. 2014;75(3):363\u201373.","journal-title":"Ann Neurol"},{"issue":"9","key":"6529_CR14","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1002\/sctm.18-0154","volume":"8","author":"L Mazzini","year":"2019","unstructured":"Mazzini L, Gelati M, Profico DC, Sorar\u00f9 G, Ferrari D, Copetti M, et al. Results from phase I clinical trial with intraspinal injection of neural stem cells in amyotrophic lateral sclerosis: A Long-Term outcome. Stem Cells Transl Med. 2019;8(9):887\u201397.","journal-title":"Stem Cells Transl Med"},{"issue":"9","key":"6529_CR15","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1038\/s41591-022-01956-3","volume":"28","author":"RH Baloh","year":"2022","unstructured":"Baloh RH, Johnson JP, Avalos P, Allred P, Svendsen S, Gowing G, et al. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1\/2a trial. Nat Med. 2022;28(9):1813\u201322.","journal-title":"Nat Med"},{"issue":"6","key":"6529_CR16","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1002\/acn3.567","volume":"5","author":"SA Goutman","year":"2018","unstructured":"Goutman SA, Brown MB, Glass JD, Boulis NM, Johe K, Hazel T, et al. Long-term phase 1\/2 intraspinal stem cell transplantation outcomes in ALS. Ann Clin Transl Neurol. 2018;5(6):730\u201340.","journal-title":"Ann Clin Transl Neurol"},{"issue":"12","key":"6529_CR17","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1016\/j.stem.2023.11.001","volume":"30","author":"MA Leone","year":"2023","unstructured":"Leone MA, Gelati M, Profico DC, Gobbi C, Pravat\u00e0 E, Copetti M, et al. Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis. Cell Stem Cell. 2023;30(12):1597\u2013e16098.","journal-title":"Cell Stem Cell"},{"issue":"9","key":"6529_CR18","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1634\/stemcells.2007-0040","volume":"25","author":"L De Filippis","year":"2007","unstructured":"De Filippis L, Lamorte G, Snyder EY, Malgaroli A, Vescovi AL. A novel, immortal, and multipotent human neural stem cell line generating functional neurons and oligodendrocytes. Stem Cells. 2007;25(9):2312\u201321.","journal-title":"Stem Cells"},{"key":"6529_CR19","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/978-1-0716-1783-0_5","volume":"2389","author":"M Gelati","year":"2022","unstructured":"Gelati M, Profico DC, Ferrari D, Vescovi AL. Culturing and expansion of clinical grade neural stem cells from the fetal human central nervous system. Methods Mol Biol. 2022;2389:57\u201366.","journal-title":"Methods Mol Biol"},{"issue":"11","key":"6529_CR20","doi-asserted-by":"publisher","first-page":"e14035","DOI":"10.1371\/journal.pone.0014035","volume":"5","author":"L Rota Nodari","year":"2010","unstructured":"Rota Nodari L, Ferrari D, Giani F, Bossi M, Rodriguez-Menendez V, Tredici G, et al. Long-term survival of human neural stem cells in the ischemic rat brain upon transient immunosuppression. PLoS ONE. 2010;5(11):e14035.","journal-title":"PLoS ONE"},{"issue":"2","key":"6529_CR21","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1038\/cmi.2016.39","volume":"14","author":"R Diehl","year":"2017","unstructured":"Diehl R, Ferrara F, M\u00fcller C, Dreyer AY, McLeod DD, Fricke S, et al. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol. 2017;14(2):146\u201379.","journal-title":"Cell Mol Immunol"},{"key":"6529_CR22","doi-asserted-by":"crossref","unstructured":"Guyenet SJ, Furrer SA, Damian VM, Baughan TD, La Spada AR, Garden GA. A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp. 2010;(39):1787.","DOI":"10.3791\/1787-v"},{"issue":"5","key":"6529_CR23","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1242\/dmm.007237","volume":"4","author":"A Acevedo-Arozena","year":"2011","unstructured":"Acevedo-Arozena A, Kalmar B, Essa S, Ricketts T, Joyce P, Kent R, et al. A comprehensive assessment of the SOD1G93A low-copy Transgenic mouse, which models human amyotrophic lateral sclerosis. Dis Models Mech. 2011;4(5):686\u2013700.","journal-title":"Dis Models Mech"},{"issue":"7","key":"6529_CR24","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/nrn2652","volume":"10","author":"SP Brooks","year":"2009","unstructured":"Brooks SP, Dunnett SB. Tests to assess motor phenotype in mice: a user\u2019s guide. Nat Rev Neurosci. 2009;10(7):519\u201329.","journal-title":"Nat Rev Neurosci"},{"key":"6529_CR25","first-page":"1","volume-title":"The mouse brain in stereotaxic coordinates","author":"G Paxinos","year":"2001","unstructured":"Paxinos G, Franklin KBJ, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic; 2001. p. 1.","edition":"2"},{"key":"6529_CR26","first-page":"57648","volume":"136","author":"K Young","year":"2018","unstructured":"Young K, Morrison H. Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ. JoVE. 2018;136:57648.","journal-title":"JoVE"},{"issue":"8","key":"6529_CR27","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/j.jcyt.2014.02.003","volume":"16","author":"M Boido","year":"2014","unstructured":"Boido M, Piras A, Valsecchi V, Spigolon G, Mareschi K, Ferrero I, et al. Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis. Cytotherapy. 2014;16(8):1059\u201372.","journal-title":"Cytotherapy"},{"key":"6529_CR28","doi-asserted-by":"crossref","unstructured":"Valsecchi V, Boido M, Montarolo F, Guglielmotto M, Perga S, Martire S et al. The transcription factor Nurr1 is up-regulated in amyotrophic lateral sclerosis patients and SOD1-G93A mice. Disease Models & Mechanisms. 2020;dmm.043513.","DOI":"10.1242\/dmm.043513"},{"issue":"21","key":"6529_CR29","doi-asserted-by":"publisher","first-page":"13425","DOI":"10.3390\/ijms232113425","volume":"23","author":"DC Profico","year":"2022","unstructured":"Profico DC, Gelati M, Ferrari D, Sgaravizzi G, Ricciolini C, Projetti Pensi M, et al. Human neural stem Cell-Based drug product: clinical and nonclinical characterization. Int J Mol Sci. 2022;23(21):13425.","journal-title":"Int J Mol Sci"},{"issue":"11","key":"6529_CR30","doi-asserted-by":"publisher","first-page":"4166","DOI":"10.1523\/JNEUROSCI.4184-10.2011","volume":"31","author":"PH Ozdinler","year":"2011","unstructured":"Ozdinler PH, Benn S, Yamamoto TH, G\u00fczel M, Brown RH, Macklis JD. Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G93A Transgenic ALS mice. J Neurosci. 2011;31(11):4166\u201377.","journal-title":"J Neurosci"},{"issue":"2","key":"6529_CR31","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.nbd.2012.03.036","volume":"47","author":"JH Jara","year":"2012","unstructured":"Jara JH, Villa SR, Khan NA, Bohn MC, Ozdinler PH. AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS. Neurobiol Dis. 2012;47(2):174\u201383.","journal-title":"Neurobiol Dis"},{"issue":"4","key":"6529_CR32","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1093\/cercor\/bhu317","volume":"26","author":"L Saba","year":"2016","unstructured":"Saba L, Viscomi MT, Caioli S, Pignataro A, Bisicchia E, Pieri M, et al. Altered functionality, morphology, and vesicular glutamate transporter expression of cortical motor neurons from a presymptomatic mouse model of amyotrophic lateral sclerosis. Cereb Cortex. 2016;26(4):1512\u201328.","journal-title":"Cereb Cortex"},{"issue":"7","key":"6529_CR33","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1007\/s00018-011-0873-5","volume":"69","author":"D Ferrari","year":"2012","unstructured":"Ferrari D, Zalfa C, Nodari LR, Gelati M, Carlessi L, Delia D, et al. Differential pathotropism of non-immortalized and immortalized human neural stem cell lines in a focal demyelination model. Cell Mol Life Sci. 2012;69(7):1193\u2013210.","journal-title":"Cell Mol Life Sci"},{"issue":"4","key":"6529_CR34","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1002\/brb3.142","volume":"3","author":"S Vinsant","year":"2013","unstructured":"Vinsant S, Mansfield C, Jimenez-Moreno R, Del Gaizo Moore V, Yoshikawa M, Hampton TG, et al. Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion. Brain Behav. 2013;3(4):431\u201357.","journal-title":"Brain Behav"},{"issue":"2","key":"6529_CR35","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1002\/acn3.51712","volume":"10","author":"A Nigri","year":"2023","unstructured":"Nigri A, Dalla Bella E, Ferraro S, Medina Carrion JP, Demichelis G, Bersano E, et al. Cervical spinal cord atrophy in amyotrophic lateral sclerosis across disease stages. Ann Clin Transl Neurol. 2023;10(2):213\u201324.","journal-title":"Ann Clin Transl Neurol"},{"issue":"2","key":"6529_CR36","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s11011-014-9539-y","volume":"30","author":"JM Ziebell","year":"2015","unstructured":"Ziebell JM, Adelson PD, Lifshitz J. Microglia: dismantling and rebuilding circuits after acute neurological injury. Metab Brain Dis. 2015;30(2):393\u2013400.","journal-title":"Metab Brain Dis"},{"issue":"4","key":"6529_CR37","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1007\/s11064-021-03499-4","volume":"47","author":"F Ullah","year":"2022","unstructured":"Ullah F, Gamage R, Sen MK, Gyengesi E. The effects of modified Curcumin preparations on glial morphology in aging and neuroinflammation. Neurochem Res. 2022;47(4):813\u201324.","journal-title":"Neurochem Res"},{"issue":"1","key":"6529_CR38","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s13287-024-03693-5","volume":"15","author":"F Virla","year":"2024","unstructured":"Virla F, Turano E, Scambi I, Schiaffino L, Boido M, Mariotti R. Administration of adipose-derived stem cells extracellular vesicles in a murine model of spinal muscular atrophy: effects of a new potential therapeutic strategy. Stem Cell Res Ther. 2024;15(1):94.","journal-title":"Stem Cell Res Ther"},{"issue":"18","key":"6529_CR39","doi-asserted-by":"publisher","first-page":"14236","DOI":"10.3390\/ijms241814236","volume":"24","author":"Y Zhang","year":"2023","unstructured":"Zhang Y, Park YS, Kim IB. A distinct microglial cell population expressing both CD86 and CD206 constitutes a dominant type and executes phagocytosis in two mouse models of retinal degeneration. IJMS. 2023;24(18):14236.","journal-title":"IJMS"},{"issue":"4","key":"6529_CR40","doi-asserted-by":"publisher","first-page":"379","DOI":"10.3390\/biomedicines9040379","volume":"9","author":"F Garello","year":"2021","unstructured":"Garello F, Boido M, Miglietti M, Bitonto V, Zenzola M, Filippi M, et al. Imaging of inflammation in spinal cord injury: novel insights on the usage of PFC-Based contrast agents. Biomedicines. 2021;9(4):379.","journal-title":"Biomedicines"},{"issue":"8","key":"6529_CR41","doi-asserted-by":"publisher","first-page":"e42614","DOI":"10.1371\/journal.pone.0042614","volume":"7","author":"MP Hefferan","year":"2012","unstructured":"Hefferan MP, Galik J, Kakinohana O, Sekerkova G, Santucci C, Marsala S, et al. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. PLoS ONE. 2012;7(8):e42614.","journal-title":"PLoS ONE"},{"issue":"7","key":"6529_CR42","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1097\/01.tp.0000235532.00920.7a","volume":"82","author":"L Xu","year":"2006","unstructured":"Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, et al. Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 Transgenic rats. Transplantation. 2006;82(7):865\u201375.","journal-title":"Transplantation"},{"issue":"3","key":"6529_CR43","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.neulet.2011.03.017","volume":"494","author":"L Xu","year":"2011","unstructured":"Xu L, Shen P, Hazel T, Johe K, Koliatsos VE. Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 Transgenic rats. Neurosci Lett. 2011;494(3):222\u20136.","journal-title":"Neurosci Lett"},{"issue":"8","key":"6529_CR44","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1634\/stemcells.2005-0518","volume":"24","author":"J Yan","year":"2006","unstructured":"Yan J, Xu L, Welsh AM, Chen D, Hazel T, Johe K, et al. Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve disease outcomes in amyotrophic lateral sclerosis Transgenic mice. Stem Cells. 2006;24(8):1976\u201385.","journal-title":"Stem Cells"},{"issue":"8","key":"6529_CR45","doi-asserted-by":"publisher","first-page":"e689","DOI":"10.1371\/journal.pone.0000689","volume":"2","author":"M Suzuki","year":"2007","unstructured":"Suzuki M, McHugh J, Tork C, Shelley B, Klein SM, Aebischer P, et al. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of Familial ALS. PLoS ONE. 2007;2(8):e689.","journal-title":"PLoS ONE"},{"key":"6529_CR46","doi-asserted-by":"crossref","unstructured":"Doneg M, Giusto E, Cossetti C, Pluchino S. Systemic Neural Stem Cell-Based Therapeutic Interventions for Inflammatory CNS Disorders. In: Bonfanti L, editor. Neural Stem Cells - New Perspectives [Internet]. InTech; 2013 [cited 2025 Mar 23]. Available from: http:\/\/www.intechopen.com\/books\/neural-stem-cells-new-perspectives\/systemic-neural-stem-cell-based-therapeutic-interventions-for-inflammatory-cns-disorders","DOI":"10.5772\/55426"},{"issue":"6","key":"6529_CR47","doi-asserted-by":"publisher","first-page":"851","DOI":"10.3727\/096368910X543411","volume":"20","author":"KP Reekmans","year":"2011","unstructured":"Reekmans KP, Praet J, De Vocht N, Tambuyzer BR, Bergwerf I, Daans J, et al. Clinical potential of intravenous neural stem cell delivery for treatment of neuroinflammatory disease in mice?? Cell Transpl. 2011;20(6):851\u201370.","journal-title":"Cell Transpl"},{"issue":"2","key":"6529_CR48","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.brainres.2004.04.038","volume":"1016","author":"K Chu","year":"2004","unstructured":"Chu K, Kim M, Park KI, Jeong SW, Park HK, Jung KH, et al. Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. Brain Res. 2004;1016(2):145\u201353.","journal-title":"Brain Res"},{"issue":"1","key":"6529_CR49","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1743-8454-5-10","volume":"5","author":"CE Johanson","year":"2008","unstructured":"Johanson CE, Duncan JA, Klinge PM, Brinker T, Stopa EG, Silverberg GD. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Fluids Barriers CNS. 2008;5(1):10.","journal-title":"Fluids Barriers CNS"},{"key":"6529_CR50","doi-asserted-by":"publisher","unstructured":"Johanson CE. Choroid Plexus\u2013Cerebrospinal Fluid Circulatory Dynamics: Impact on Brain Growth, Metabolism, and Repair. In: Conn PM, editor. Neuroscience in Medicine [Internet]. Totowa, NJ: Humana Press; 2008 [cited 2025 Mar 23]. pp. 173\u2013200. Available from: http:\/\/link.springer.com\/https:\/\/doi.org\/10.1007\/978-1-60327-455-5_11","DOI":"10.1007\/978-1-60327-455-5_11"},{"issue":"12","key":"6529_CR51","doi-asserted-by":"publisher","first-page":"3526","DOI":"10.1093\/brain\/awaa309","volume":"143","author":"BE Clarke","year":"2020","unstructured":"Clarke BE, Patani R. The microglial component of amyotrophic lateral sclerosis. Brain. 2020;143(12):3526\u201339.","journal-title":"Brain"},{"issue":"4","key":"6529_CR52","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/nrn3710","volume":"15","author":"GC Brown","year":"2014","unstructured":"Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci. 2014;15(4):209\u201316.","journal-title":"Nat Rev Neurosci"},{"issue":"19","key":"6529_CR53","doi-asserted-by":"publisher","first-page":"3224","DOI":"10.1093\/hmg\/ddaa209","volume":"29","author":"W Liu","year":"2020","unstructured":"Liu W, Taso O, Wang R, Bayram S, Graham AC, Garcia-Reitboeck P, et al. Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions. Hum Mol Genet. 2020;29(19):3224\u201348.","journal-title":"Hum Mol Genet"},{"issue":"4","key":"6529_CR54","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1007\/s00401-020-02193-z","volume":"140","author":"F Cignarella","year":"2020","unstructured":"Cignarella F, Filipello F, Bollman B, Cantoni C, Locca A, Mikesell R, et al. TREM2 activation on microglia promotes Myelin debris clearance and remyelination in a model of multiple sclerosis. Acta Neuropathol. 2020;140(4):513\u201334.","journal-title":"Acta Neuropathol"},{"issue":"1","key":"6529_CR55","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41593-021-00975-6","volume":"25","author":"M Xie","year":"2022","unstructured":"Xie M, Liu YU, Zhao S, Zhang L, Bosco DB, Pang YP, et al. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat Neurosci. 2022;25(1):26\u201338.","journal-title":"Nat Neurosci"},{"key":"6529_CR56","doi-asserted-by":"publisher","first-page":"815347","DOI":"10.3389\/fnagi.2022.815347","volume":"14","author":"S Guo","year":"2022","unstructured":"Guo S, Wang H, Yin Y. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci. 2022;14:815347.","journal-title":"Front Aging Neurosci"},{"key":"6529_CR57","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.omtm.2021.03.017","volume":"21","author":"Y Ciervo","year":"2021","unstructured":"Ciervo Y, Gatto N, Allen C, Grierson A, Ferraiuolo L, Mead RJ, et al. Adipose-derived stem cells protect motor neurons and reduce glial activation in both in vitro and in vivo models of ALS. Mol Therapy - Methods Clin Dev. 2021;21:413\u201333.","journal-title":"Mol Therapy - Methods Clin Dev"},{"issue":"3","key":"6529_CR58","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.nbd.2008.05.016","volume":"31","author":"A Vercelli","year":"2008","unstructured":"Vercelli A, Mereuta OM, Garbossa D, Muraca G, Mareschi K, Rustichelli D, et al. Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2008;31(3):395\u2013405.","journal-title":"Neurobiol Dis"},{"issue":"3","key":"6529_CR59","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.neulet.2009.10.074","volume":"468","author":"H Kim","year":"2010","unstructured":"Kim H, Kim HY, Choi MR, Hwang S, Nam KH, Kim HC, et al. Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett. 2010;468(3):190\u20134.","journal-title":"Neurosci Lett"},{"key":"6529_CR60","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.scr.2017.11.005","volume":"25","author":"F Sironi","year":"2017","unstructured":"Sironi F, Vallarola A, Violatto MB, Talamini L, Freschi M, De Gioia R, et al. Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice. Stem Cell Res. 2017;25:166\u201378.","journal-title":"Stem Cell Res"},{"key":"6529_CR61","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.neulet.2014.05.001","volume":"574","author":"MY Noh","year":"2014","unstructured":"Noh MY, Cho KA, Kim H, Kim SM, Kim SH. Erythropoietin modulates the immune-inflammatory response of a SOD1(G93A) Transgenic mouse model of amyotrophic lateral sclerosis (ALS). Neurosci Lett. 2014;574:53\u20138.","journal-title":"Neurosci Lett"},{"issue":"7","key":"6529_CR62","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1002\/stem.2825","volume":"36","author":"GM Thomsen","year":"2018","unstructured":"Thomsen GM, Avalos P, Ma AA, Alkaslasi M, Cho N, Wyss L, et al. Transplantation of neural progenitor cells expressing glial cell Line-Derived neurotrophic factor into the motor cortex as a strategy to treat amyotrophic lateral sclerosis. Stem Cells. 2018;36(7):1122\u201331.","journal-title":"Stem Cells"},{"issue":"47","key":"6529_CR63","doi-asserted-by":"publisher","first-page":"15587","DOI":"10.1523\/JNEUROSCI.2037-14.2014","volume":"34","author":"GM Thomsen","year":"2014","unstructured":"Thomsen GM, Gowing G, Latter J, Chen M, Vit JP, Staggenborg K, et al. Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex. J Neurosci. 2014;34(47):15587\u2013600.","journal-title":"J Neurosci"},{"issue":"1","key":"6529_CR64","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s13024-023-00665-w","volume":"18","author":"M Xie","year":"2023","unstructured":"Xie M, Pallegar PN, Parusel S, Nguyen AT, Wu LJ. Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms. Mol Neurodegener. 2023;18(1):75.","journal-title":"Mol Neurodegener"},{"key":"6529_CR65","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12967-014-0371-2","volume":"13","author":"L Mazzini","year":"2015","unstructured":"Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Projetti Pensi M, Muzi G, et al. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med. 2015;13:17.","journal-title":"J Transl Med"},{"issue":"10","key":"6529_CR66","doi-asserted-by":"publisher","first-page":"e25968","DOI":"10.1371\/journal.pone.0025968","volume":"6","author":"AC Lepore","year":"2011","unstructured":"Lepore AC, O\u2019Donnell J, Kim AS, Williams T, Tuteja A, Rao MS, et al. Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS. PLoS ONE. 2011;6(10):e25968.","journal-title":"PLoS ONE"},{"issue":"165","key":"6529_CR67","doi-asserted-by":"publisher","first-page":"165ra164","DOI":"10.1126\/scitranslmed.3004579","volume":"4","author":"YD Teng","year":"2012","unstructured":"Teng YD, Benn SC, Kalkanis SN, Shefner JM, Onario RC, Cheng B, et al. Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis. Sci Transl Med. 2012;4(165):165ra164.","journal-title":"Sci Transl Med"},{"issue":"3","key":"6529_CR68","doi-asserted-by":"publisher","first-page":"115382","DOI":"10.1016\/j.celrep.2025.115382","volume":"44","author":"OI Kahn","year":"2025","unstructured":"Kahn OI, Dominguez SL, Glock C, Hayne M, Vito S, Sengupta Ghosh A, et al. Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation. Cell Rep. 2025;44(3):115382.","journal-title":"Cell Rep"},{"issue":"1","key":"6529_CR69","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1080\/17482960701856300","volume":"9","author":"S Scott","year":"2008","unstructured":"Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler. 2008;9(1):4\u201315.","journal-title":"Amyotroph Lateral Scler"},{"issue":"8001","key":"6529_CR70","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/s41586-024-07042-7","volume":"626","author":"M Hruska-Plochan","year":"2024","unstructured":"Hruska-Plochan M, Wiersma VI, Betz KM, Mallona I, Ronchi S, Maniecka Z, et al. A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature. 2024;626(8001):1073\u201383.","journal-title":"Nature"},{"issue":"3","key":"6529_CR71","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/s41587-023-01784-x","volume":"42","author":"X Hu","year":"2024","unstructured":"Hu X, White K, Olroyd AG, DeJesus R, Dominguez AA, Dowdle WE, et al. Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques. Nat Biotechnol. 2024;42(3):413\u201323.","journal-title":"Nat Biotechnol"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-06529-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-025-06529-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-06529-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T16:02:49Z","timestamp":1746806569000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-025-06529-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["6529"],"URL":"https:\/\/doi.org\/10.1186\/s12967-025-06529-9","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,9]]},"assertion":[{"value":"14 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All the experimental protocols involving live animals were performed in strict accordance with institutional guidelines in compliance with national (D.L. N.26, 04\/03\/2014) and international law and policies (new directive 2010\/63\/EU). The studies on nude and SOD1G93A mice following hNSC ICV transplantation: additional microglial markers mice were approved by the Italian Ministry of Health (#751\/2019-PR and #391\/2021-PR protocols, respectively). Additionally, the ad hoc Institutional Animal Welfare Committee (OPBA) of the University of Milano-Bicocca and the Ethical Committee of the University of Turin approved these studies. The tissue specimen for hNSCs derivation was obtained under the approval of the ethical committee of the Institute \u201cCasa Sollievo della Sofferenza di San Pio da Pietrelcina\u201d, complying with the Helsinki declaration (WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects) and with the parents\u2019 informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"During the preparation of this work the authors used ChatGPT to check grammar. After using this tool\/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Generative AI and AI-assisted technologies in the writing process"}},{"value":"All the authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"529"}}