{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T20:00:26Z","timestamp":1788292826420,"version":"build-2803163510"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001823","name":"Ministerstvo \u0160kolstv\u00ed, Ml\u00e1de\u017ee a T\u011blov\u00fdchovy","doi-asserted-by":"publisher","award":["CZ.02.01.01\/00\/22_008\/0004562"],"award-info":[{"award-number":["CZ.02.01.01\/00\/22_008\/0004562"]}],"id":[{"id":"10.13039\/501100001823","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["24-11193S"],"award-info":[{"award-number":["24-11193S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V002694"],"award-info":[{"award-number":["MR\/V002694"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Spinal cord injury involves complex pathobiological mechanisms, necessitating a multidimensional approach for its cure. Previous studies have shown that \u03b19-integrin expression and activation in mature dorsal root ganglion neurons enable the regeneration of injured axons within the spinal cord. However, tissue cavitation and fibrosis impede the regenerating axons from following their usual pathways, forcing them to seek alternative routes rich in tenascin-C, the primary ligand of the integrin. Fibrin gel, an FDA-approved and biocompatible material, can offer three-dimensional support for axonal extension through the cavitated area, thus preventing the formation of aberrant paths and connections that occur in the absence of a suitable scaffold.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The aim of this study was to investigate how combining \u03b19-integrin expression by adeno-associated virus with the use of a fibrin gel as an extracellular microenvironment affects the growth of mature DRG neurites <jats:italic>in vitro<\/jats:italic>. Additionally, we sought to functionalize fibrin with integrin ligand peptides, specifically AEIDGIEL, the active domain of tenascin-C, to ensure \u03b19-integrin activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results indicate that fibrin gels are a suitable biomaterial for promoting neurite growth and that AEIDGIEL peptide effectively activates the integrin. Furthermore, we corroborate an autocrine signaling loop of \u03b19-integrin and TN-C produced by neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>the proposed combination therapy of \u03b19-integrin and fibrin gel biomaterials incorporating AEIDGIEL peptide shows promise for addressing the complex challenges of spinal cord injury and promoting effective neural regeneration, laying the foundation for further <jats:italic>in vivo<\/jats:italic> research.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncel.2025.1568004","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T05:38:36Z","timestamp":1743485916000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined strategy of \u03b1 9-integrin transduction and AEIDGIEL peptide-functionalized fibrin gel biomaterials to promote mature DRG neurite growth"],"prefix":"10.3389","volume":"19","author":[{"given":"Anda","family":"Cimpean","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Roll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Reinhard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica C. F.","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Faissner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"de Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Fawcett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavla","family":"Jendelov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"B1","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. Primer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5546","DOI":"10.1523\/jneurosci.0759-09.2009","article-title":"\u03b19 integrin promotes neurite outgrowth on tenascin-c and enhances sensory axon regeneration.","volume":"29","author":"Andrews","year":"2009","journal-title":"J. Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1211066","DOI":"10.3389\/fnins.2023.1211066","article-title":"Hydrogel scaffolds in the treatment of spinal cord injury: A review.","volume":"17","author":"Cai","year":"2023","journal-title":"Front. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"7283","DOI":"10.1523\/jneurosci.0901-16.2016","article-title":"Expression of an activated integrin promotes long-distance sensory axon regeneration in the spinal cord.","volume":"36","author":"Cheah","year":"2016","journal-title":"J. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"4775","DOI":"10.1523\/jneurosci.2076-22.2023","article-title":"Integrin-driven axon regeneration in the spinal cord activates a distinctive CNS regeneration program.","volume":"43","author":"Cheah","year":"2023","journal-title":"J. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2271","DOI":"10.1002\/jbm.a.35754","article-title":"Aprotinin extends mechanical integrity time of cell-seeded fibrin sutures.","volume":"104","author":"Coffin","year":"2016","journal-title":"J. Biomed. Mater. Res. A"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1097\/BRS.0000000000004417","article-title":"Spinal cord injury: The global incidence, prevalence, and disability from the global burden of disease study 2019.","volume":"47","author":"Ding","year":"2022","journal-title":"Spine"},{"key":"B8","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1007\/s11064-019-02844-y","article-title":"The struggle to make CNS axons regenerate: Why has it been so difficult?","volume":"45","author":"Fawcett","year":"2020","journal-title":"Neurochem. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1002\/dneu.20950","article-title":"Integrins and the extracellular matrix: Key mediators of development and regeneration of the sensory nervous system.","volume":"71","author":"Gardiner","year":"2011","journal-title":"Dev. Neurobiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/s12951-022-01541-3","article-title":"Biocompatible exosome-modified fibrin gel accelerates the recovery of spinal cord injury by VGF-mediated oligodendrogenesis.","volume":"20","author":"He","year":"2022","journal-title":"J. Nanobiotechnol."},{"key":"B11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/(SICI)1097-4636(19980615)40:4<551::AID-JBM6>3.0.CO;2-E","article-title":"Effects of fibrin micromorphology on neurite growth from dorsal root ganglia cultured in three-dimensional fibrin gels.","volume":"40","author":"Herbert","year":"1998","journal-title":"J. Biomed. Mater. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41392-023-01477-6","article-title":"Spinal cord injury: Molecular mechanisms and therapeutic interventions.","volume":"8","author":"Hu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e0239242","DOI":"10.1371\/journal.pone.0239242","article-title":"Increasing salinity of fibrinogen solvent generates stable fibrin hydrogels for cell delivery or tissue engineering.","volume":"16","author":"Jarrell","year":"2021","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1016\/j.biomaterials.2007.01.008","article-title":"Enhanced neurite growth from mammalian neurons in three-dimensional salmon fibrin gels.","volume":"28","author":"Ju","year":"2007","journal-title":"Biomaterials"},{"key":"B15","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.biomaterials.2010.08.109","article-title":"Engineered aprotinin for improved stability of fibrin biomaterials.","volume":"32","author":"Lorentz","year":"2011","journal-title":"Biomaterials"},{"key":"B16","doi-asserted-by":"publisher","first-page":"18124","DOI":"10.1038\/s41598-021-97604-w","article-title":"Thermosensitive collagen\/fibrinogen gels loaded with decorin suppress lesion site cavitation and promote functional recovery after spinal cord injury.","volume":"11","author":"Matthews","year":"2021","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"108981","DOI":"10.1016\/j.jneumeth.2020.108981","article-title":"Liposomes embedded within fibrin gels facilitate localized macrophage manipulations within nerve.","volume":"348","author":"Pan","year":"2021","journal-title":"J. Neurosci. Methods"},{"key":"B18","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1021\/bc9800769","article-title":"Cross-linking exogenous bifunctional peptides into fibrin gels with factor XIIIa.","volume":"10","author":"Schense","year":"1999","journal-title":"Bioconjug. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.actbio.2017.07.013","article-title":"Fibrin functionalization with synthetic adhesive ligands interacting with \u03b16\u03b21 integrin receptor enhance neurite outgrowth of embryonic stem cell-derived neural stem\/progenitors.","volume":"59","author":"Silva","year":"2017","journal-title":"Acta Biomater."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1523\/jneurosci.15-03-01971.1995","article-title":"Tenascin knockout mice: Barrels, boundary molecules, and glial scars.","volume":"15","author":"Steindler","year":"1995","journal-title":"J. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.24.534172","article-title":"Alpha 9 integrin expression enables reconstruction of the spinal cord sensory pathway.","author":"Stepankova","year":"2023","journal-title":"bioRxiv [Preprint]"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1016\/j.biomaterials.2004.04.045","article-title":"Mechanical properties, proteolytic degradability and biological modifications affect angiogenic process extension into native and modified fibrin matrices in vitro.","volume":"26","author":"Urech","year":"2005","journal-title":"Biomaterials"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-4939-7522-8_1","article-title":"Small scale production of recombinant adeno-associated viral vectors for gene delivery to the nervous system","author":"Verhaagen","year":"2018","journal-title":"Retinal Gene Therapy"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1822","DOI":"10.1523\/JNEUROSCI.20-05-01822.2000","article-title":"Impaired axonal regeneration in \u03b17 integrin-deficient mice.","volume":"20","author":"Werner","year":"2000","journal-title":"J. Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2101663","DOI":"10.1002\/adhm.202101663","article-title":"Biomimetic scaffolds for spinal cord applications exhibit stiffness-dependent immunomodulatory and neurotrophic characteristics.","volume":"11","author":"Woods","year":"2022","journal-title":"Adv. Healthc. Mater."},{"key":"B26","doi-asserted-by":"publisher","first-page":"11423","DOI":"10.1074\/jbc.273.19.11423","article-title":"Identification of the ligand binding site for the integrin \u03b19\u03b21 in the third fibronectin type III repeat of tenascin-C.","volume":"273","author":"Yokosaki","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13036-020-00244-3","article-title":"Application of fibrin-based hydrogels for nerve protection and regeneration after spinal cord injury.","volume":"14","author":"Yu","year":"2020","journal-title":"J. Biol. Eng."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2025.1568004\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T05:38:53Z","timestamp":1743485933000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2025.1568004\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":27,"alternative-id":["10.3389\/fncel.2025.1568004"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2025.1568004","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,1]]},"article-number":"1568004"}}