{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:41:08Z","timestamp":1787506868380,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2021MH205"],"award-info":[{"award-number":["ZR2021MH205"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Scaffold materials, neurotrophic factors, and seed cells are three elements of neural tissue engineering. As well-known self-assembling peptide-based hydrogels, RADA16-I and modified peptides are attractive matrices for neural tissue engineering. In addition to its neuroprotective effects, cerebral dopamine neurotrophic factor (CDNF) has been reported to promote the proliferation, migration, and differentiation of neural stem cells (NSCs). However, the role of RADA16-I combined with CDNF on NSCs remains unknown. First, the effect of RADA16-I hydrogel and CDNF on the proliferation and differentiation of cultured NSCs was investigated. Next, RADA16-I hydrogel and CDNF were microinjected into the lateral ventricle (LV) of middle cerebral artery occlusion (MCAO) rats to activate endogenous NSCs. CDNF promoted the proliferation of NSCs, while RADA16-I induced the neural differentiation of NSCs in vitro. Importantly, both RADA16-I and CDNF promoted the proliferation, migration, and differentiation of endogenous NSCs by activating the ERK1\/2 and STAT3 pathways, and CDNF exerted an obvious neuroprotective effect on brain ischemia-reperfusion injury. These findings provide new information regarding the application of the scaffold material RADA16-I hydrogel and the neurotrophic factor CDNF in neural tissue engineering and suggest that RADA16-I hydrogel and CDNF microinjection may represent a novel therapeutic strategy for the treatment of stroke.<\/jats:p>","DOI":"10.3390\/ijms23031436","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T22:00:56Z","timestamp":1643320856000},"page":"1436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The Effect of RADA16-I and CDNF on Neurogenesis and Neuroprotection in Brain Ischemia-Reperfusion Injury"],"prefix":"10.3390","volume":"23","author":[{"given":"Xingyu","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyuan","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1146\/annurev.bioeng.5.011303.120731","article-title":"Neural tissue engineering: Strategies for repair and regeneration","volume":"5","author":"Schmidt","year":"2003","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.addr.2007.03.014","article-title":"Approaches to neural tissue engineering using scaffolds for drug delivery","volume":"59","author":"Willerth","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.csbj.2018.10.011","article-title":"Hydrogel-assisted neuroregeneration approaches towards brain injury therapy: A state-of-the-art review","volume":"16","author":"Kornev","year":"2018","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8414","DOI":"10.1073\/pnas.0407843102","article-title":"Dynamic reassembly of peptide RADA16 nanofiber scaffold","volume":"102","author":"Yokoi","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/1475-925X-9-70","article-title":"Effect of 3D-scaffold formation on differentiation and survival in human neural progenitor cells","volume":"9","author":"Ortinau","year":"2010","journal-title":"Biomed. Eng. Online"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1002\/term.1512","article-title":"Three-dimensional growth matrix for human embryonic stem cell-derived neuronal cells","volume":"8","author":"Joki","year":"2014","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.nano.2008.12.001","article-title":"Self-assembling peptide nanofiber scaffold promotes the reconstruction of acutely injured brain","volume":"5","author":"Guo","year":"2009","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/j.biomaterials.2012.11.043","article-title":"Neural stem cells encapsulated in a functionalized self-assembling peptide hydrogel for brain tissue engineering","volume":"34","author":"Cheng","year":"2013","journal-title":"Biomaterials"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1021\/acsbiomaterials.6b00156","article-title":"Self-Assembling Peptide Nanofiber Scaffolds for 3-D Reprogramming and Transplantation of Human Pluripotent Stem Cell-Derived Neurons","volume":"2","author":"Francis","year":"2016","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/dneu.20760","article-title":"Novel CDNF\/MANF family of neurotrophic factors","volume":"70","author":"Lindholm","year":"2010","journal-title":"Dev. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1177\/01926230701481899","article-title":"Reprint: Six-Month Continuous Intraputamenal Infusion Toxicity Study of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHuGDNF) in Rhesus Monkeys","volume":"35","author":"Hovland","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/ana.20737","article-title":"Randomized controlled trial of intraputamenal glial cell line\u2013derived neurotrophic factor infusion in Parkinson disease","volume":"59","author":"Lang","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1385\/JMN:20:2:173","article-title":"MANF\u2014A new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons","volume":"20","author":"Petrova","year":"2003","journal-title":"J. Mol. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nature05957","article-title":"Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo","volume":"448","author":"Lindholm","year":"2007","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9651","DOI":"10.1523\/JNEUROSCI.0833-09.2009","article-title":"Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson\u2019s disease","volume":"29","author":"Voutilainen","year":"2009","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, G.-L., Wang, L.-H., Liu, X.-Y., Zhang, Y.-X., Hu, M.-Y., Liu, L., Fang, Y.-Y., Mu, Y., Zhao, Y., and Huang, S.-H. (2018). Cerebral Dopamine Neurotrophic Factor (CDNF) Has Neuroprotective Effects against Cerebral Ischemia That May Occur through the Endoplasmic Reticulum Stress Pathway. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071905"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.ymthe.2017.09.019","article-title":"MANF promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke","volume":"26","author":"Tseng","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_18","first-page":"139","article-title":"Effect of cerebral dopamine neurotrophic factor on endogenous neural progenitor cell migration in a rat model of Parkinson\u2019s disease","volume":"18","author":"Nasrolahi","year":"2019","journal-title":"EXCLI J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.4103\/1673-5374.282262","article-title":"Cerebral dopamine neurotrophic factor promotes the proliferation and differentiation of neural stem cells in hypoxic environments","volume":"15","author":"Lin","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1126\/science.1553558","article-title":"Generation of neurons and astrocytes from isolated cells of the adult mammalian central-nervous-system","volume":"255","author":"Reynolds","year":"1992","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/372263a0","article-title":"A self-renewing multipotential stem-cell in embryonic rat cerebral-cortex","volume":"372","author":"Davis","year":"1994","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/35102174","article-title":"The development of neural stem cells","volume":"414","author":"Temple","year":"2001","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0959-4388(03)00017-5","article-title":"Neurogenesis after ischaemic brain insults","volume":"13","author":"Kokaia","year":"2003","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0306-4522(01)00117-8","article-title":"Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia","volume":"105","author":"Zhang","year":"2001","journal-title":"Neuroscience"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.expneurol.2010.08.006","article-title":"Increased subventricular zone-derived cortical neurogenesis after ischemic lesion","volume":"226","author":"Kreuzberg","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0092-8674(90)90662-X","article-title":"Cns stem-cells express a new class of intermediate filament protein","volume":"60","author":"Lendahl","year":"1990","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1523\/JNEUROSCI.22-03-00629.2002","article-title":"Neurogenesis in adult subventricular zone","volume":"22","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S1044-7431(03)00159-3","article-title":"Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum","volume":"24","author":"Jin","year":"2003","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1172\/JCI200420001","article-title":"Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury","volume":"113","author":"Sun","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1097\/00004647-200404000-00009","article-title":"Activated Neural Stem Cells Contribute to Stroke-Induced Neurogenesis and Neuroblast Migration toward the Infarct Boundary in Adult Rats","volume":"24","author":"Zhang","year":"2004","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1634\/stemcells.2005-0281","article-title":"Persistent Production of Neurons from Adult Brain Stem Cells During Recovery after Stroke","volume":"24","author":"Thored","year":"2006","journal-title":"Stem. Cells"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1038\/sj.jcbfm.9600432","article-title":"Monocyte Chemoattractant Protein-1 Plays a Critical Role in Neuroblast Migration after Focal Cerebral Ischemia","volume":"27","author":"Yan","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"16281","DOI":"10.1039\/C7NR06528K","article-title":"Effects of an injectable functionalized self-assembling nanopeptide hydrogel on angiogenesis and neurogenesis for regeneration of the central nervous system","volume":"9","author":"Wang","year":"2017","journal-title":"Nanoscale"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s12257-009-3076-2","article-title":"Compatibility of Neural Stem Cells with Functionalized Self-assembling Peptide Scaffold In vitro","volume":"15","author":"Zhang","year":"2010","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/neuro.16.001.2010","article-title":"Glycine-spacers influence functional motifs exposure and self-assembling propensity of functionalized substrates tailored for neural stem cell cultures","volume":"3","author":"Taraballi","year":"2010","journal-title":"Front. Neuroeng."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.neuron.2011.05.004","article-title":"Lake-front property: A unique germinal niche by the lateral ventricles of the adult brain","volume":"70","author":"Ihrie","year":"2011","journal-title":"Neuron"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"ENEURO.0214-17.2017","DOI":"10.1523\/ENEURO.0214-17.2017","article-title":"MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex","volume":"4","author":"Tseng","year":"2017","journal-title":"Eneuro"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/jbm.a.32707","article-title":"Neural differentiation directed by self-assembling peptide scaffolds presenting laminin-derived epitopes","volume":"94","author":"Li","year":"2010","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1083\/jcb.200503021","article-title":"Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin","volume":"172","author":"Ng","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Zhou, L., and Too, H.-P. (2011). Mitochondrial Localized STAT3 Is Involved in NGF Induced Neurite Outgrowth. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021680"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1006\/exnr.2000.7508","article-title":"Differential Patterns of ERK and STAT3 Phosphorylation after Sciatic Nerve Transection in the Rat","volume":"166","author":"Sheu","year":"2000","journal-title":"Exp. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1083\/jcb.134.3.689","article-title":"Role for gelsolin in actuating epidermal growth factor receptor-mediated cell motility","volume":"134","author":"Chen","year":"1996","journal-title":"J. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"30688","DOI":"10.1074\/jbc.272.49.30688","article-title":"Platelet-derived growth factor and fibronectin-stimulated migration are differentially regulated by the Rac and extracellular signal-regulated kinase pathways","volume":"272","author":"Zetter","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4619","DOI":"10.1242\/jcs.01481","article-title":"MAP kinases and cell migration","volume":"117","author":"Huang","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/ncb1094","article-title":"FAK\u2013Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly","volume":"6","author":"Webb","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/cne.22039","article-title":"Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats","volume":"515","author":"Airavaara","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.ijdevneu.2011.05.012","article-title":"A comparison of proliferative capacity and passaging potential between neural stem and progenitor cells in adherent and neurosphere cultures","volume":"29","author":"Sun","year":"2011","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ijdevneu.2013.12.001","article-title":"Gypenosides pre-treatment protects the brain against cerebral ischemia and increases neural stem cells\/progenitors in the subventricular zone","volume":"33","author":"Wang","year":"2014","journal-title":"Int. J. Dev. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1436\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:08:43Z","timestamp":1760134123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031436"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031436","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,27]]}}}