{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:51:17Z","timestamp":1785919877541,"version":"3.56.0"},"reference-count":69,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":216,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Stem Cells International"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This systematic review and meta\u2010analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed\/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi\u2010experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non\u2010controlled pre\u2013post studies with 460 participants. Heterogeneity was evaluated using\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      statistics, and subgroup analyses were conducted based on treatment duration and dosing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A pooled analysis (treatment group:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200993; control group:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200990) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12\u201313.67;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.0003), which was beneficial for both the \u226510\u2009\u00d7\u200910\n                      <jats:sup>6<\/jats:sup>\n                      and &lt;10\u2009\u00d7\u200910\n                      <jats:sup>6<\/jats:sup>\n                      dose sub\u2010groups. However, a meta\u2010analysis of single\u2010arm studies in two control (pre\u2010intervention) and intervention phases (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200988) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: \u22121.27 (\u22123.01 to 0.47);\n                      <jats:italic>p<\/jats:italic>\n                      = 0.15), month 6 (WMD: \u22122.69 (\u22125.62 to 0.25);\n                      <jats:italic>p<\/jats:italic>\n                      = 0.07), month 9 (WMD: \u22121.55 (\u22123.49 to 0.39);\n                      <jats:italic>p<\/jats:italic>\n                      = 0.12), and month 12 (WMD: \u22127.59 (\u221213.95 to \u22121.26);\n                      <jats:italic>p<\/jats:italic>\n                      = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: \u221210.91; 95% CI: \u221216.39 to \u22125.43;\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.0001) and month 6 (WMD: \u221215.97; 95% CI: \u221228.60 to \u22123.33;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.01) compared with the pre\u2010intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high\u2010dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: \u22128.10 (\u221218.25 to 2.06);\n                      <jats:italic>p<\/jats:italic>\n                      = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high\u2010dose groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large\u2010scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow\u2010up periods.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/sci\/4122493","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:28:33Z","timestamp":1785918513000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta\u2010Analysis"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3252-2842","authenticated-orcid":false,"given":"Mahdieh","family":"Pourasghari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0259-2866","authenticated-orcid":false,"given":"Soraya","family":"Babaie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2710-7345","authenticated-orcid":false,"given":"Raha","family":"Markazi-Movaghar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0238-0889","authenticated-orcid":false,"given":"Saba","family":"Salehpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1804-7793","authenticated-orcid":false,"given":"Bina","family":"Eftekharsadat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5754-4613","authenticated-orcid":false,"given":"Azizeh","family":"Farshbaf-Khalili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"e_1_2_13_1_2","first-page":"1","volume-title":"Proteostasis: Investigating Molecular Dynamics in Neurodegenerative Disorders","author":"Verma M.","year":"2025"},{"key":"e_1_2_13_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-023-02728-6"},{"key":"e_1_2_13_3_2","first-page":"471","volume-title":"Encyclopedia of Tissue Engineering and Regenerative Medicine","author":"Selvaraj S.","year":"2019"},{"key":"e_1_2_13_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2016.03.024"},{"key":"e_1_2_13_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.11.002"},{"key":"e_1_2_13_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-024-05229-9"},{"key":"e_1_2_13_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.1054573"},{"key":"e_1_2_13_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25990"},{"key":"e_1_2_13_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-021-05291-2"},{"key":"e_1_2_13_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00012-5"},{"key":"e_1_2_13_11_2","doi-asserted-by":"publisher","DOI":"10.1017\/cjn.2021.30"},{"key":"e_1_2_13_12_2","doi-asserted-by":"publisher","DOI":"10.14740\/jocmr2495w"},{"key":"e_1_2_13_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41536-021-00131-5"},{"key":"e_1_2_13_14_2","unstructured":"WorkentinM. 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