{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T23:33:18Z","timestamp":1774222398785,"version":"3.50.1"},"reference-count":67,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-75-30007"],"award-info":[{"award-number":["19-75-30007"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nerve tissue damage is an unsolved problem in modern neurology and neurosurgery, which prompts the need to search for approaches to stimulate neuroprotection and regeneration of neural tissue. Earlier we have shown that the secretome of human mesenchymal stromal cells (MSCs) stimulates rat survival, reduces the severity of neurological deficits, and decreases the volume of brain damage in a hemorrhagic stroke model. A significant disadvantage of using the MSC secretome is the need to concentrate it (at least 5\u201310 fold) to achieve appreciable pharmacological activity. This increases the cost of obtaining clinically applicable amounts of secretome and slows down the clinical translation of this technology. Here, we created a number of genetically modified human MSC cultures, including immortalized MSCs and those with hyperexpression of brain-derived neurotrophic factor (BDNF) and urokinase-type plasminogen activator (uPA) and with suppressed expression of Von Hippel\u2013Lindau tumor suppressor (VHL), and we evaluated the pharmacological activity of their secretomes in a model of intracerebral hemorrhage (ICH) in rats. The secretome of MSCs immortalized by hyperexpression of the catalytic subunit of human telomerase (hTERT) revealed neuroprotective activity indistinguishable from that of primary MSC cultures, yet it still required 10-fold concentration to achieve neuroprotective efficacy. The secretome of MSC culture with combined hyperexpression of BDNF and uPA and suppressed expression of Von Hippel\u2013Lindau tumor suppressor even without additional concentration reduced the severity of neurological disorders and decreased brain lesion volume in the ICH model. The secretomes of MSCs with separate overexpression of BDNF and uPA or suppression of VHL had no such effect or, on the contrary, revealed a toxic effect in the ICH model. Presumably, this may be due to an imbalance in the representation of individual growth factors in the secretome of genetically modified MSCs, which individually may lead to undesirable effects in damaged nervous tissue, such as increased permeability of the blood\u2013brain barrier (under the influence of pro-angiogenic factors) or neural cell apoptosis (due to an excess of neurotrophic factors). The obtained data show that genetic modification of MSC cultures can enhance or alter the therapeutic activity of their secretomes, which can be used in the creation of promising sources of biopharmaceutical substances.<\/jats:p>","DOI":"10.3390\/ijms26146697","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T10:55:41Z","timestamp":1752490541000},"page":"6697","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Overexpression of BDNF and uPA Combined with the Suppression of Von Hippel\u2013Lindau Tumor Suppressor Enhances the Neuroprotective Activity of the Secretome of Human Mesenchymal Stromal Cells in the Model of Intracerebral Hemorrhage"],"prefix":"10.3390","volume":"26","author":[{"given":"Stalik S.","family":"Dzhauari","sequence":"first","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1386-5922","authenticated-orcid":false,"given":"Alexandra L.","family":"Primak","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2597-8879","authenticated-orcid":false,"given":"Nataliya A.","family":"Basalova","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3497-9619","authenticated-orcid":false,"given":"Natalia I.","family":"Kalinina","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna O.","family":"Monakova","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirill D.","family":"Bozov","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3686-0072","authenticated-orcid":false,"given":"Arkadiy Ya.","family":"Velichko","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria E.","family":"Illarionova","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga A.","family":"Grigorieva","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhanna A.","family":"Akopyan","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir S.","family":"Popov","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel G.","family":"Malkov","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0696-1369","authenticated-orcid":false,"given":"Anastasia Yu.","family":"Efimenko","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vsevolod A.","family":"Tkachuk","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4289-3428","authenticated-orcid":false,"given":"Maxim N.","family":"Karagyaur","sequence":"additional","affiliation":[{"name":"Medical Research and Education Institute, Lomonosov Moscow State University, 27\/1, Lomonosovsky Ave., 119191 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1134\/S0006297919110087","article-title":"Biochemical Mechanisms and Translational Relevance of Hippocampal Vulnerability to Distant Focal Brain Injury: The Price of Stress Response","volume":"84","author":"Gulyaeva","year":"2019","journal-title":"Biochemistry (Moscow)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1134\/S0006297921020048","article-title":"Glucocorticoids: Dr. Jekyll and Mr. Hyde of Hippocampal Neuroinflammation","volume":"86","author":"Bolshakov","year":"2021","journal-title":"Biochemistry (Moscow)"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.25259\/SNI_773_2023","article-title":"Neuroprotection strategies in traumatic brain injury: Studying the effectiveness of different clinical approaches","volume":"15","author":"Buccilli","year":"2024","journal-title":"Surg. Neurol. Int."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Karagyaur, M., Dzhauari, S., Basalova, N., Aleksandrushkina, N., Sagaradze, G., Danilova, N., Malkov, P., Popov, V., Skryabina, M., and Efimenko, A. (2021). MSC Secretome as a Promising Tool for Neuroprotection and Neuroregeneration in a Model of Intracerebral Hemorrhage. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122031"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1479-5876-9-10","article-title":"Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning","volume":"9","author":"Efimenko","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Petrenko, Y., Vackova, I., Kekulova, K., Chudickova, M., Koci, Z., Turnovcova, K., Kupcova Skalnikova, H., Vodicka, P., and Kubinova, S. (2020). A Comparative Analysis of Multipotent Mesenchymal Stromal Cells derived from Different Sources, with a Focus on Neuroregenerative Potential. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-61167-z"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/ana.25493","article-title":"Cell therapy for ischemic stroke: Are differences in preclinical and clinical study design responsible for the translational loss of efficacy?","volume":"86","author":"Cui","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Li, W., Shi, L., Hu, B., Hong, Y., Zhang, H., Li, X., and Zhang, Y. (2021). Mesenchymal Stem Cell-Based Therapy for Stroke: Current Understanding and Challenges. Front. Cell. Neurosci., 15.","DOI":"10.3389\/fncel.2021.628940"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dzhauari, S., Basalova, N., Primak, A., Balabanyan, V., Efimenko, A., Skryabina, M., Popov, V., Velichko, A., Bozov, K., and Akopyan, Z. (2023). The Secretome of Mesenchymal Stromal Cells in Treating Intracerebral Hemorrhage: The First Step to Bedside. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15061608"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Primak, A., Kalinina, N., Skryabina, M., Usachev, V., Chechekhin, V., Vigovskiy, M., Chechekhina, E., Voloshin, N., Kulebyakin, K., and Kulebyakina, M. (2024). Novel Immortalized Human Multipotent Mesenchymal Stromal Cell Line for Studying Hormonal Signaling. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042421"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1089\/biores.2012.0252","article-title":"Constitutive expression of human telomerase enhances the proliferation potential of human mesenchymal stem cells","volume":"1","author":"Bischoff","year":"2012","journal-title":"Biores. Open Access"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1161\/CIRCRESAHA.113.301690","article-title":"Transplantation of mesenchymal cells rejuvenated by the overexpression of telomerase and myocardin promotes revascularization and tissue repair in a murine model of hindlimb ischemia","volume":"113","author":"Madonna","year":"2013","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1385\/MN:27:3:277","article-title":"Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury","volume":"27","author":"Boyd","year":"2003","journal-title":"Mol. Neurobiol."},{"key":"ref_14","unstructured":"Gomazkov, O.A. (2006). Neurotrophic Regulation and Brain Stem Cells, Publishing House \u201cIcarus\u201d."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4336","DOI":"10.1523\/JNEUROSCI.21-12-04336.2001","article-title":"Induction of the plasminogen activator system accompanies peripheral nerve regeneration after sciatic nerve crush","volume":"21","author":"Siconolfi","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4269","DOI":"10.1523\/JNEUROSCI.09-12-04269.1989","article-title":"Neuronal Plasminogen Activators: Cell Surface Binding Sites and Involvement in Neurite Outgrowth","volume":"9","author":"Pittman","year":"1989","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dzhauari, S., Litvinova, S., Efimenko, A., Aleksandrushkina, N., Basalova, N., Abakumov, M., Danilova, N., Malkov, P., Balabanyan, V., and Bezuglova, T. (2022). Urokinase-Type Plasminogen Activator Enhances the Neuroprotective Activity of Brain-Derived Neurotrophic Factor in a Model of Intracerebral Hemorrhage. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061346"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.1093\/emboj\/19.16.4298","article-title":"Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein","volume":"19","author":"Tanimoto","year":"2000","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/sj.cdd.4402313","article-title":"The VHL tumor suppressor and HIF: Insights from genetic studies in mice","volume":"15","author":"Kapitsinou","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3895","DOI":"10.2174\/138161209789649394","article-title":"The VHL tumor suppressor: Master regulator of HIF","volume":"15","author":"Haase","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mel\u00e9ndez-Rodr\u00edguez, F., Roche, O., Sanchez-Prieto, R., and Aragones, J. (2018). Hypoxia-Inducible Factor 2-Dependent Pathways Driving Von Hippel-Lindau-Deficient Renal Cancer. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00214"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zimna, A., and Kurpisz, M. (2015). Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies. Biomed Res Int., 2015.","DOI":"10.1155\/2015\/549412"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bakleh, M.Z., and Al Haj Zen, A. (2025). The Distinct Role of HIF-1\u03b1 and HIF-2\u03b1 in Hypoxia and Angiogenesis. Cells, 14.","DOI":"10.3390\/cells14090673"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.yjmcc.2007.04.001","article-title":"HIF-1alpha induced-VEGF overexpression in bone marrow stem cells protects cardiomyocytes against ischemia","volume":"42","author":"Dai","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.tranon.2014.02.003","article-title":"The role of angiopoietins as potential therapeutic targets in renal cell carcinoma","volume":"7","author":"Wang","year":"2014","journal-title":"Transl. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23036","DOI":"10.18632\/oncotarget.4564","article-title":"HIF2a inhibitors for the treatment of VHL disease","volume":"6","author":"Metelo","year":"2015","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1046\/j.1469-7580.2000.19740591.x","article-title":"VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy","volume":"197","author":"Hobson","year":"2000","journal-title":"J. Anat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1172\/JCI20682","article-title":"VEGF: A critical player in neurodegeneration","volume":"113","author":"Storkebaum","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.stem.2008.08.003","article-title":"A high-efficiency system for the generation and study of human induced pluripotent stem cells","volume":"3","author":"Maherali","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.virusres.2008.06.004","article-title":"Structure and function of HCV IRES domains","volume":"139","author":"Lukavsky","year":"2009","journal-title":"Virus Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1124\/jpet.119.261594","article-title":"A Bicistronic Plasmid Encoding Brain-Derived Neurotrophic Factor and Urokinase Plasminogen Activator Stimulates Peripheral Nerve Regeneration After Injury","volume":"372","author":"Karagyaur","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.joca.2012.11.010","article-title":"Effects of doxycycline on mesenchymal stem cell chondrogenesis and cartilage repair","volume":"21","author":"Lee","year":"2013","journal-title":"Osteoarthr Cartil."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Voloshin, N., Tyurin-Kuzmin, P., Karagyaur, M., Akopyan, Z., and Kulebyakin, K. (2023). Practical Use of Immortalized Cells in Medicine: Current Advances and Future Perspectives. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612716"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1016\/j.bbapap.2013.01.032","article-title":"Stem cells: Insights into the secretome","volume":"1834","author":"Makridakis","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/s13287-015-0209-8","article-title":"Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes","volume":"6","author":"Kalinina","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1186\/s13287-021-02596-z","article-title":"Applications, challenges and prospects of mesenchymal stem cell exosomes in regenerative medicine","volume":"12","author":"Rezabakhsh","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_37","first-page":"16","article-title":"Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access","volume":"29","author":"Giovannelli","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6430565","DOI":"10.1155\/2022\/6430565","article-title":"Immortalized Mesenchymal Stem Cells: A Safe Cell Source for Cellular or Cell Membrane-Based Treatment of Glioma","volume":"2022","author":"Zhang","year":"2022","journal-title":"Stem Cells Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s11055-024-01648-0","article-title":"The Secretome of Mesenchymal Stromal Cells as a New Hope in the Treatment of Acute Brain Tissue Injuries","volume":"54","author":"Primak","year":"2024","journal-title":"Neurosci. Behav. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Shahror, R.A., Wu, C.C., Chiang, Y.H., and Chen, K.Y. (2020). Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114051"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16053","DOI":"10.1038\/mtm.2016.53","article-title":"Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia","volume":"3","author":"Beegle","year":"2016","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lopatina, T., Kalinina, N., Karagyaur, M., Stambolsky, D., Rubina, K., Revischin, A., Pavlova, G., Parfyonova, Y., and Tkachuk, V. (2019). Correction: Adipose-Derived Stem Cells Stimulate Regeneration of Peripheral Nerves: BDNF Secreted by These Cells Promotes Nerve Healing and Axon Growth De Novo. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0219946"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1016\/j.biochi.2013.06.020","article-title":"The stem cell secretome and its role in brain repair","volume":"95","author":"Drago","year":"2013","journal-title":"Biochimie"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1177\/0271678X18776802","article-title":"The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke","volume":"38","author":"Cunningham","year":"2018","journal-title":"J. Cerebr. Blood Flow Metab."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kim, H.J., Bayarsaikhan, D., Lee, J., Bayarsaikhan, G., and Lee, B. (2021). Brain-Derived Neurotrophic Factor Secreting Human Mesenchymal Stem Cells Improve Outcomes in Rett Syndrome Mouse Models. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.725398"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"20677","DOI":"10.3402\/jev.v2i0.20677","article-title":"Distinct RNA profiles in subpopulations of extracellular vesicles: Apoptotic bodies, microvesicles and exosomes","volume":"2","author":"Crescitelli","year":"2013","journal-title":"J. Extracell. Vesicles"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Guduric-Fuchs, J., O\u2019Connor, A., Camp, B., O\u2019Neill, C.L., Medina, R.J., and Simpson, D.A. (2012). Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genom., 13.","DOI":"10.1186\/1471-2164-13-357"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e1008371","DOI":"10.1080\/2162402X.2015.1008371","article-title":"Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment","volume":"4","author":"Ridder","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1134\/S1819712423040074","article-title":"State-of-the-Art: The Use of Extracellular Vesicles and Preparations Based on Them for Neuroprotection and Stimulation of Brain Tissue Regeneration after Injury","volume":"17","author":"Basalova","year":"2023","journal-title":"Neurochem. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"111338","DOI":"10.1016\/j.brainresbull.2025.111338","article-title":"Dysregulation of proBDNF\/p75NTR and BDNF\/TrkB Signaling in Acute Ischemic Stroke: Different Sides of the Same Coins","volume":"226","author":"Alnoaman","year":"2025","journal-title":"Brain Res. Bull."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41398-021-01667-2","article-title":"proBDNF expression induces apoptosis and inhibits synaptic regeneration by regulating the RhoA-JNK pathway in an in vitro post-stroke depression model","volume":"11","author":"Yang","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1759091420930865","DOI":"10.1177\/1759091420930865","article-title":"Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice","volume":"12","author":"Montroull","year":"2020","journal-title":"ASN Neuro"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"C1148","DOI":"10.1152\/ajpcell.1999.276.5.C1148","article-title":"VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase\/cGMP-dependent pathway","volume":"276","author":"Mayhan","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1172\/JCI9369","article-title":"VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain","volume":"106","author":"Zhang","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"647","DOI":"10.14336\/AD.2021.1121","article-title":"VEGF, a Key Factor for Blood Brain Barrier Injury After Cerebral Ischemic Stroke","volume":"13","author":"Hu","year":"2022","journal-title":"Aging Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/cns.13082","article-title":"Amyloid beta soluble forms and plasminogen activation system in Alzheimer\u2019s disease: Consequences on extracellular maturation of brain-derived neurotrophic factor and therapeutic implications","volume":"25","author":"Angelucci","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.bbadis.2017.01.023","article-title":"Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer\u2019s neuropathology and cognitive deficits","volume":"1863","author":"Gerenu","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.jcyt.2019.08.002","article-title":"Mesenchymal Stem versus Stromal Cells: International Society for Cell & Gene Therapy (ISCT\u00ae) Mesenchymal Stromal Cell Committee Position Statement on Nomenclature","volume":"21","author":"Viswanathan","year":"2019","journal-title":"Cytotherapy"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Tyurin-Kuzmin, P.A., Karagyaur, M.N., Kulebyakin, K.Y., Dyikanov, D.T., Chechekhin, V.I., Ivanova, A.M., Skryabina, M.N., Arbatskiy, M.S., Sysoeva, V.Y., and Kalinina, N.I. (2020). Functional Heterogeneity of Protein Kinase A Activation in Multipotent Stromal Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124442"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1089\/104303401753153947","article-title":"Systematic determination of the packaging limit of lentiviral vectors","volume":"12","author":"Kumar","year":"2001","journal-title":"Hum. Gene Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.omtm.2021.04.007","article-title":"The impact of lentiviral vector genome size and producer cell genomic to gag-pol mRNA ratios on packaging efficiency and titre","volume":"21","author":"Sweeney","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Sagaradze, G., Grigorieva, O., Nimiritsky, P., Basalova, N., Kalinina, N., Akopyan, Z., and Efimenko, A. (2019). Conditioned Medium from Human Mesenchymal Stromal Cells: Towards the Clinical Translation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071656"},{"key":"ref_64","first-page":"765","article-title":"Method of modeling local hemorrhage in various structures of the brain in experimental animals","volume":"52","author":"Makarenko","year":"2002","journal-title":"IP Pavlov. J. Higher Nerv. Act."},{"key":"ref_65","unstructured":"Paxinos, G., and Watson, C. (2007). The Rat Brain in Stereotaxic Coordinates, 6th Edition, Academic Press."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1161\/01.STR.7.5.485","article-title":"Cerebral infarction in the Mongolian gerbil exacerbated by phenoxyben-zamine treatment","volume":"7","author":"McGraw","year":"1976","journal-title":"Stroke"},{"key":"ref_67","first-page":"22","article-title":"Brain blood circulation in different types of cerebral circulatory hypoxia","volume":"9","author":"Gannushkina","year":"2000","journal-title":"Bull. Russ. Acad. Med. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6697\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:08:59Z","timestamp":1760033339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,12]]},"references-count":67,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146697"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146697","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,12]]}}}