{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T17:43:24Z","timestamp":1785606204050,"version":"3.56.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004089","name":"Krembil Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004089","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Spinal cord injury (SCI) elicits a hostile microenvironment characterized by inflammation, gliosis, and disrupted signaling pathways that collectively impede neural repair. Neural progenitor cells (NPCs) represent a promising regenerative approach, yet their survival and differentiation are often compromised in this setting. Here, we investigated whether engineering NPCs to overexpress the Notch pathway modulator Delta-like non-canonical Notch ligand 1 (DLK1) could overcome these limitations and improve functional outcomes after cervical SCI in rats. NPCs were engineered to express DLK1 under a Pax6 promoter-driven expression system, ensuring elevated DLK1 levels during the progenitor state. Following transplantation of DLK1-overexpressing NPCs or control NPCs, we assessed graft survival, lineage differentiation, behavioral performance, and electrophysiological integration over 12 weeks. DLK1-expressing NPCs exhibited significantly greater retention in the injured spinal cord and showed enhanced neuronal differentiation alongside reduced astrocytic commitment compared to controls. Behavioral tests\u2014including forelimb grip strength and CatWalk gait assessments\u2014demonstrated that DLK1-modified NPCs conferred robust improvements in forelimb motor coordination and overall locomotion. Concordantly, electrophysiological recordings revealed increased motor-evoked potential amplitudes and area-under-the-curve values in animals receiving DLK1-transduced NPC grafts, indicative of strengthened synaptic integration within the host motor circuitry.<\/jats:p>","DOI":"10.1093\/stcltm\/szaf014","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T16:15:07Z","timestamp":1748708107000},"source":"Crossref","is-referenced-by-count":1,"title":["DLK1-expressing neural progenitor cells promote tissue repair and functional recovery after cervical spinal cord injury"],"prefix":"10.1093","volume":"14","author":[{"given":"Nader","family":"Hejrati","sequence":"first","affiliation":[{"name":"Division of Genetics and Development, Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]},{"name":"Department of Neurosurgery, HOCH health Ostschweiz, Cantonal Hospital St. Gallen , St. Gallen ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Lou","sequence":"additional","affiliation":[{"name":"Division of Genetics and Development, Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]},{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON M5S 1A8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sogolie","family":"Kouhzaei","sequence":"additional","affiliation":[{"name":"Division of Genetics and Development, Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Genetics and Development, Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]},{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON M5S 1A8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Genetics and Development, Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Khazaei","sequence":"additional","affiliation":[{"name":"Division of Genetics and Development, Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]},{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON M5S 1A8 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5722-6364","authenticated-orcid":false,"given":"Michael G","family":"Fehlings","sequence":"additional","affiliation":[{"name":"Division of Genetics and Development, Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]},{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON M5S 1A8 ,","place":["Canada"]},{"name":"Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto , Toronto, ON M5T 1P5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"2025053112150100000_CIT0001","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.coph.2021.08.009","article-title":"A review of emerging neuroprotective and neuroregenerative therapies in traumatic spinal cord injury","volume":"60","author":"Hejrati","year":"2021","journal-title":"Curr Opin Pharmacol"},{"key":"2025053112150100000_CIT0002","doi-asserted-by":"publisher","first-page":"17018","DOI":"10.1038\/nrdp.2017.18","article-title":"Traumatic spinal cord injury","volume":"3","author":"Ahuja","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"2025053112150100000_CIT0003","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1093\/brain\/awad392","article-title":"Neural stem cell therapies for spinal cord injury repair: an update on recent preclinical and clinical advances","volume":"147","author":"Hosseini","year":"2024","journal-title":"Brain"},{"key":"2025053112150100000_CIT0004","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1756-6606-6-3","article-title":"Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury","volume":"6","author":"Nishimura","year":"2013","journal-title":"Mol Brain"},{"key":"2025053112150100000_CIT0005","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1111\/jnc.14833","article-title":"Inhibition of Notch1 signaling promotes neuronal differentiation and improves functional recovery in spinal cord injury through suppressing the activation of Ras homolog family member A","volume":"150","author":"Peng","year":"2019","journal-title":"J Neurochem"},{"key":"2025053112150100000_CIT0006","doi-asserted-by":"publisher","first-page":"4548","DOI":"10.7150\/thno.71378","article-title":"NOTCH1 signaling regulates the latent neurogenic program in adult reactive astrocytes after spinal cord injury","volume":"12","author":"Tan","year":"2022","journal-title":"Theranostics"},{"key":"2025053112150100000_CIT0007","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1186\/s13287-020-01724-5","article-title":"Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1\/Notch pathway","volume":"11","author":"Zhou","year":"2020","journal-title":"Stem Cell Res Ther"},{"key":"2025053112150100000_CIT0008","doi-asserted-by":"publisher","first-page":"3010","DOI":"10.1080\/15384101.2019.1667189","article-title":"Blocking Notch signal pathway suppresses the activation of neurotoxic A1 astrocytes after spinal cord injury","volume":"18","author":"Qian","year":"2019","journal-title":"Cell Cycle"},{"key":"2025053112150100000_CIT0009","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.cellsig.2016.01.003","article-title":"Evidence of non-canonical NOTCH signaling: Delta-like 1 homolog (DLK1) directly interacts with the NOTCH1 receptor in mammals","volume":"28","author":"Traustad\u00f3ttir","year":"2016","journal-title":"Cell Signal"},{"key":"2025053112150100000_CIT0010","doi-asserted-by":"publisher","first-page":"2437","DOI":"10.1634\/stemcells.2005-0661","article-title":"Concise Review: Notch Signaling in Stem Cell Systems","volume":"24","author":"Chiba","year":"2006","journal-title":"Stem Cells"},{"key":"2025053112150100000_CIT0011","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1210\/er.2006-0046","article-title":"Notch Signaling in Development and Cancer","volume":"28","author":"Bol\u00f3s","year":"2007","journal-title":"Endocr Rev"},{"key":"2025053112150100000_CIT0012","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/nn1475","article-title":"Notch signaling in the mammalian central nervous system: insights from mouse mutants","volume":"8","author":"Yoon","year":"2005","journal-title":"Nat Neurosci"},{"key":"2025053112150100000_CIT0013","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/s0896-6273(01)00179-9","article-title":"Notch1 and Notch3 Instructively Restrict bFGF-Responsive Multipotent Neural Progenitor Cells to an Astroglial Fate","volume":"29","author":"Tanigaki","year":"2001","journal-title":"Neuron"},{"key":"2025053112150100000_CIT0014","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1369\/00221554211048951","article-title":"Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness","volume":"70","author":"Grassi","year":"2022","journal-title":"J Histochem Cytochem"},{"key":"2025053112150100000_CIT0015","doi-asserted-by":"publisher","first-page":"5421","DOI":"10.1128\/MCB.02437-05","article-title":"Ectodomain Shedding of Preadipocyte Factor 1 (Pref-1) by Tumor Necrosis Factor Alpha Converting Enzyme (TACE) and Inhibition of Adipocyte Differentiation","volume":"26","author":"Wang","year":"2006","journal-title":"Mol Cell Biol"},{"key":"2025053112150100000_CIT0016","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s12015-011-9298-7","article-title":"DLK1 promotes neurogenesis of human and mouse pluripotent stem cell-derived neural progenitors via modulating notch and bmp signalling","volume":"8","author":"Surmacz","year":"2012","journal-title":"Stem Cell RevRep"},{"key":"2025053112150100000_CIT0017","doi-asserted-by":"publisher","first-page":"6115","DOI":"10.3390\/ijms23116115","article-title":"Thirty years\u2019 history since the discovery of pax6: from central nervous system development to neurodevelopmental disorders","volume":"23","author":"Ochi","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025053112150100000_CIT0018","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nbt.1529","article-title":"Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling","volume":"27","author":"Chambers","year":"2009","journal-title":"Nat Biotechnol"},{"key":"2025053112150100000_CIT0019","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1093\/ilar.48.4.385","article-title":"Rat models of traumatic spinal cord injury to assess motor recovery","volume":"48","author":"Onifer","year":"2007","journal-title":"ILAR J"},{"key":"2025053112150100000_CIT0020","doi-asserted-by":"publisher","first-page":"3377","DOI":"10.1523\/JNEUROSCI.4184-05.2006","article-title":"Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury","volume":"26","author":"Karimi-Abdolrezaee","year":"2006","journal-title":"J Neurosci"},{"key":"2025053112150100000_CIT0021","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1038\/nn.2377","article-title":"Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation","volume":"12","author":"Garc\u00eda-Al\u00edas","year":"2009","journal-title":"Nat Neurosci"},{"key":"2025053112150100000_CIT0022","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/0014-4886(87)90299-8","article-title":"A behavioral and anatomical analysis of spinal cord injury produced by a feedback-controlled impaction device","volume":"95","author":"Bresnahan","year":"1987","journal-title":"Exp Neurol"},{"key":"2025053112150100000_CIT0023","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1097\/BRS.0b013e3182269732","article-title":"Assessment of gait in a rat model of myofascial inflammation using the CatWalk system","volume":"36","author":"Miyagi","year":"2011","journal-title":"Spine"},{"key":"2025053112150100000_CIT0024","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3233\/RNN-2011-0583","article-title":"Delayed rehabilitation with task-specific therapies improves forelimb function after a cervical spinal cord injury","volume":"29","author":"Dai","year":"2011","journal-title":"Restor Neurol Neurosci"},{"key":"2025053112150100000_CIT0025","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nature10229","article-title":"Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis","volume":"475","author":"Ferr\u00f3n","year":"2011","journal-title":"Nature"},{"key":"2025053112150100000_CIT0026","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3389\/fncel.2020.00078","article-title":"Dissecting the dual role of the glial scar and scar-forming astrocytes in spinal cord injury","volume":"14","author":"Yang","year":"2020","journal-title":"Front Cell Neurosci"},{"key":"2025053112150100000_CIT0027","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s10571-024-01519-9","article-title":"The role of inflammatory cascade and reactive astrogliosis in glial scar formation post-spinal cord injury","volume":"44","author":"Bhatt","year":"2024","journal-title":"Cell Mol Neurobiol"},{"key":"2025053112150100000_CIT0028","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1242\/dev.00374","article-title":"Delta-Notch signaling controls the generation of neurons\/glia from neural stem cells in a stepwise process","volume":"130","author":"Grandbarbe","year":"2003","journal-title":"Development"},{"key":"2025053112150100000_CIT0029","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1038\/s41583-020-0314-2","article-title":"Transplanting neural progenitor cells to restore connectivity after spinal cord injury","volume":"21","author":"Fischer","year":"2020","journal-title":"Nat Rev Neurosci"},{"issue":"525","key":"2025053112150100000_CIT0030","doi-asserted-by":"crossref","first-page":"eaau3538","DOI":"10.1126\/scitranslmed.aau3538","article-title":"GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents","volume":"12","author":"Khazaei","year":"2020","journal-title":"Sci Transl Med"},{"key":"2025053112150100000_CIT0031","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.1002\/eji.201545514","article-title":"DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR-activated murine macrophages","volume":"45","author":"Gonz\u00e1lez","year":"2015","journal-title":"Eur J Immunol"},{"issue":"9","key":"2025053112150100000_CIT0032","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1080\/14712598.2023.2245321","article-title":"How can clinical safety and efficacy concerns in stem cell therapy for spinal cord injury be overcome","volume":"23","author":"Hejrati","year":"2023","journal-title":"Expert Opin Biol Ther"},{"key":"2025053112150100000_CIT0033","doi-asserted-by":"publisher","first-page":"6854","DOI":"10.1523\/JNEUROSCI.0144-23.2023","article-title":"Notch signaling plays a dual role in regulating the neuron-to-oligodendrocyte switch in the developing dorsal forebrain","volume":"43","author":"Tran","year":"2023","journal-title":"J Neurosci"},{"key":"2025053112150100000_CIT0034","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1002\/jnr.10364","article-title":"Notch signaling promotes astrogliogenesis via direct CSL-mediated glial gene activation","volume":"69","author":"Ge","year":"2002","journal-title":"J Neurosci Res"},{"key":"2025053112150100000_CIT0035","doi-asserted-by":"publisher","first-page":"3982","DOI":"10.1128\/MCB.00170-07","article-title":"Cross talk between notch and growth factor\/cytokine signaling pathways in neural stem cells","volume":"27","author":"Nagao","year":"2007","journal-title":"Mol Cell Biol"},{"key":"2025053112150100000_CIT0036","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1111\/j.1471-4159.2007.05037.x","article-title":"Delta-like 1 participates in the specification of ventral midbrain progenitor derived dopaminergic neurons","volume":"104","author":"Bauer","year":"2008","journal-title":"J Neurochem"},{"key":"2025053112150100000_CIT0037","doi-asserted-by":"publisher","first-page":"e2015505118","DOI":"10.1073\/pnas.2015505118","article-title":"Dlk1 dosage regulates hippocampal neurogenesis and cognition","volume":"118","author":"Montalb\u00e1n-Loro","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025053112150100000_CIT0038","doi-asserted-by":"publisher","first-page":"3849","DOI":"10.1242\/dev.024570","article-title":"Selection of differentiating cells by different levels of delta-like 1 among neural precursor cells in the developing mouse telencephalon","volume":"135","author":"Kawaguchi","year":"2008","journal-title":"Development"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/14\/6\/szaf014\/63412238\/szaf014.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/14\/6\/szaf014\/63412238\/szaf014.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T16:15:08Z","timestamp":1748708108000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/doi\/10.1093\/stcltm\/szaf014\/8154547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,31]]},"references-count":38,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,5,31]]}},"URL":"https:\/\/doi.org\/10.1093\/stcltm\/szaf014","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,5,31]]},"article-number":"szaf014"}}