{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:50:09Z","timestamp":1791874209640,"version":"4.3.4"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Higher Education","award":["FSEE-2025-0015"],"award-info":[{"award-number":["FSEE-2025-0015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>It has been previously shown that some short peptides are involved in various cellular processes, such as transcription modulation and regulation of differentiation mechanisms. In particular, the effect of peptides on the neuronal differentiation of human periodontal ligament stem cells has been demonstrated. The goal of this study was to assess the effect of KED, EDR, and AEDG short peptides in stimulating the transdifferentiation of fetal MSCs into induced neuronal cells and prevention of their senescence. We applied a novel in vitro technique for neuronal cell generation, which combines the use of microRNAs, transcription factors, and small molecules to transdifferentiate fetal mesenchymal stem cells into induced cortical neurons. It was shown that the application of AEDG and KED short peptides at the end of the transdifferentiation process decreases the expression of the cell cycle marker p21 by 15% and beta-galactosidase activity by 1.51\u20132.4 times. However, short peptides did not affect the expression levels of TUj-1 and LaminB1, whose expression also changes during neuronal differentiation. The experiments indicate the potential of AEDG and KED short peptides as modulators of neurogenesis and geroprotectors and suggest that they can be used as stimulators of neuronal differentiation.<\/jats:p>","DOI":"10.3390\/cimb47090739","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Influence of Short Peptides on Cell Senescence and Neuronal Differentiation"],"prefix":"10.3390","volume":"47","author":[{"given":"Elena","family":"Sakhenberg","sequence":"first","affiliation":[{"name":"Institute of Cytology RAS, Tikhoretski Ave., 4, 194064 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5156-5421","authenticated-orcid":false,"given":"Natalia","family":"Linkova","sequence":"additional","affiliation":[{"name":"The Department of Hospital Surgery, Belgorod National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1318-3868","authenticated-orcid":false,"given":"Nina","family":"Kraskovskaya","sequence":"additional","affiliation":[{"name":"Institute of Cytology RAS, Tikhoretski Ave., 4, 194064 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7147-1884","authenticated-orcid":false,"given":"Daria","family":"Krieger","sequence":"additional","affiliation":[{"name":"Institute of Cytology RAS, Tikhoretski Ave., 4, 194064 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8682-9909","authenticated-orcid":false,"given":"Victoria","family":"Polyakova","sequence":"additional","affiliation":[{"name":"The Department of Hospital Surgery, Belgorod National Research University, 308015 Belgorod, Russia"},{"name":"The Department of Social Rehabilitation and Occupational Therapy of the St. Petersburg Medical and Social Institute, Kondratievsky St., 72A, 195271 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7401-258X","authenticated-orcid":false,"given":"Dmitrii","family":"Medvedev","sequence":"additional","affiliation":[{"name":"The Department of Social Rehabilitation and Occupational Therapy of the St. Petersburg Medical and Social Institute, Kondratievsky St., 72A, 195271 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Krasichkov","sequence":"additional","affiliation":[{"name":"Department of Radio Engineering Systems, Electrotechnical University \u201cLETI\u201d, 5F Prof. Popova St., 197022 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8293-6368","authenticated-orcid":false,"given":"Mikhail","family":"Khotin","sequence":"additional","affiliation":[{"name":"Institute of Cytology RAS, Tikhoretski Ave., 4, 194064 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Ryzhak","sequence":"additional","affiliation":[{"name":"St. Petersburg Institute of Bioregulation and Gerontology, 3 Dynamo Ave., 197110 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.stem.2023.08.001","article-title":"Chemical reprogramming for cell fate manipulation: Methods, applications, and perspectives","volume":"30","author":"Wang","year":"2023","journal-title":"Cell Stem Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1126\/science.aao5056","article-title":"Live imaging of neurogenesis in the adult mouse hippocampus","volume":"359","author":"Pilz","year":"2018","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41593-020-00759-4","article-title":"Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging","volume":"24","author":"Bottes","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Morales, A.V., and Mira, H. (2019). Adult Neural Stem Cells: Born to Last. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00096"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.tcb.2014.07.003","article-title":"Adult neurogenesis: Bridging the gap between mice and humans","volume":"24","author":"Jessberger","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lazarov, O., and Marr, R.A. (2013). Of mice and men: Neurogenesis. cognition and Alzheimer\u2019s disease. Front. Aging Neurosci., 5.","DOI":"10.3389\/fnagi.2013.00043"},{"key":"ref_7","first-page":"163","article-title":"Neural regeneration","volume":"367","author":"Steward","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Carter, J.L., Halmai, J., and Fink, K.D. (2020). The iNs and Outs of Direct Reprogramming to Induced Neurons. Front. Genome Ed., 2.","DOI":"10.3389\/fgeed.2020.00007"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e18648","DOI":"10.7554\/eLife.18648","article-title":"Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts","volume":"5","author":"Huh","year":"2016","journal-title":"Elife"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biol., 14.","DOI":"10.1186\/gb-2013-14-10-r115"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3164\/jcbn.15-39","article-title":"Highly efficient direct conversion of human fibroblasts to neuronal cells by chemical compounds","volume":"56","author":"Dai","year":"2015","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.stem.2015.06.003","article-title":"Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons","volume":"17","author":"Li","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/nature08797","article-title":"Direct conversion of fibroblasts to functional neurons by defined factors","volume":"463","author":"Vierbuchen","year":"2010","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/cr.2011.181","article-title":"Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells","volume":"22","author":"Liu","year":"2012","journal-title":"Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/mp.2015.161","article-title":"Generation of functional human serotonergic neurons from fibroblasts","volume":"21","author":"Vadodaria","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101984","DOI":"10.1016\/j.scr.2020.101984","article-title":"MicroRNAs and Ascl1 facilitate direct conversion of porcine fibroblasts into induced neurons","volume":"48","author":"Habekost","year":"2020","journal-title":"Stem Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-1-0716-1084-8_6","article-title":"Generation of Human Neurons by microRNA-Mediated Direct Conversion of Dermal Fibroblasts","volume":"2239","author":"Church","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.stem.2011.07.002","article-title":"Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions","volume":"9","author":"Ambasudhan","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nature10323","article-title":"MicroRNA-mediated conversion of human fibroblasts to neurons","volume":"476","author":"Yoo","year":"2011","journal-title":"Nature"},{"key":"ref_20","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":"ref_21","doi-asserted-by":"crossref","unstructured":"Suzuki, M., McHugh, J., Tork, C., Shelley, B., Klein, S.M., Aebischer, P., and Svendsen, C.N. (2007). GDNF secreting human neural progenitor cells protect dying motor neurons. but not their projection to muscle, in a rat model of familial ALS. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000689"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.33594\/000000096","article-title":"BDNF and NT3 Reprogram Human Ectomesenchymal Dental Pulp Stem Cells to Neurogenic and Gliogenic Neural Crest Progenitors Cultured in Serum-Free Medium","volume":"52","author":"Luzuriaga","year":"2019","journal-title":"Cell Physiol. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"El Ouaamari, Y., Van den Bos, J., Willekens, B., Cools, N., and Wens, I. (2023). Neurotrophic Factors as Regenerative Therapy for Neurodegenerative Diseases: Current Status, Challenges and Future Perspectives. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043866"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s007020170067","article-title":"Antiapoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons","volume":"108","author":"Hartbauer","year":"2001","journal-title":"J. Neural Transm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2058738419828613","DOI":"10.1177\/2058738419828613","article-title":"Effect of short peptides on neuronal differentiation of stem cells","volume":"33","author":"Caputi","year":"2019","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Medvedeva, E.V., Dmitrieva, V.G., Povarova, O.V., Limborska, S.A., Skvortsova, V.I., Myasoedov, N.F., and Dergunova, L.V. (2014). The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: Genome-wide transcriptional analysis. BMC Genom., 15.","DOI":"10.1186\/1471-2164-15-228"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0304-3940(01)01994-2","article-title":"Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax. an adrenocorticotropic hormone analog","volume":"308","author":"Shadrina","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_28","first-page":"1210","article-title":"Penetration of short fluorescence-labeled peptides into the nucleus in HeLa cells and in vitro specific interaction of the peptides with deoxyribooligonucleotides and DNA","volume":"76","author":"Fedoreyeva","year":"2011","journal-title":"Biochemistry"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kraskovskaya, N., Linkova, N., Sakhenberg, E., Krieger, D., Polyakova, V., Medvedev, D., Krasichkov, A., Khotin, M., and Ryzhak, G. (2024). Short Peptides Protect Fibroblast-Derived Induced Neurons from Age-Related Changes. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111363"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ilina, A., Khavinson, V., Linkova, N., and Petukhov, M. (2022). Neuroepigenetic Mechanisms of Action of Ultrashort Peptides in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084259"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Khavinson, V., Ilina, A., Kraskovskaya, N., Linkova, N., Kolchina, N., Mironova, E., Erofeev, A., and Petukhov, M. (2021). Neuroprotective Effects of Tripeptides\u2014Epigenetic Regulators in Mouse Model of Alzheimer\u2019s Disease. Pharmaceuticals, 14, Correction in Pharmaceuticals 2025, 18, 111.","DOI":"10.3390\/ph18010111"},{"key":"ref_32","first-page":"5","article-title":"Comparative characteristics of new mesenchymal stem cell lines derived from human embryonic stem cells, bone marrow and foreskin","volume":"54","author":"Krylova","year":"2012","journal-title":"Tsitologiia"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kraskovskaya, N., Bolshakova, A., Khotin, M., Bezprozvanny, I., and Mikhailova, N. (2023). Protocol Optimization for Direct Reprogramming of Primary Human Fibroblast into Induced Striatal Neurons. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076799"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Shlush, L.I., Itzkovitz, S., Cohen, A., Rutenberg, A., Berkovitz, R., Yehezkel, S., Shahar, H., Selig, S., and Skorecki, K. (2011). Quantitative digital in situ senescence-associated beta-galactosidase assay. BMC Cell Biol., 12.","DOI":"10.1186\/1471-2121-12-16"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Castelli, V., Benedetti, E., Antonosante, A., Catanesi, M., Pitari, G., Ippoliti, R., Cimini, A., and d\u2019Angelo, M. (2019). Neuronal Cells Rearrangement During Aging and Neurodegenerative Disease: Metabolism. Oxidative Stress and Organelles Dynamic. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00132"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1126\/science.1211222","article-title":"Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells","volume":"334","author":"Kim","year":"2011","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1091\/mbc.E15-05-0307","article-title":"Lamin B1 protein is required for dendrite development in primary mouse cortical neurons","volume":"27","author":"Giacomini","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1091\/mbc.e11-10-0884","article-title":"Lamin B1 loss is a senescence-associated biomarker","volume":"23","author":"Freund","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1111\/j.1460-9568.2007.05450.x","article-title":"Differential expression of nuclear lamin. the major component of nuclear lamina, during neurogenesis in two germinal regions of adult rat brain","volume":"25","author":"Takamori","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41420-018-0081-2","article-title":"Effects of p21 on adult hippocampal neuronal development after irradiation","volume":"4","author":"Li","year":"2018","journal-title":"Cell Death Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.stem.2012.12.001","article-title":"Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression","volume":"12","author":"Porlan","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ticli, G., Cazzalini, O., Stivala, L.A., and Prosperi, E. (2022). Revisiting the Function of p21(CDKN1A) in DNA Repair: The Influence of Protein Interactions and Stability. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137058"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1111\/j.1474-9726.2012.00870.x","article-title":"Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response","volume":"11","author":"Jurk","year":"2012","journal-title":"Aging Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-59745-361-5_3","article-title":"Methods to detect biomarkers of cellular senescence: The senescence-associated beta-galactosidase assay","volume":"371","author":"Itahana","year":"2007","journal-title":"Methods Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1124\/mol.105.016675","article-title":"Heme deficiency is associated with senescence and causes suppression of N-methyl-D-aspartate receptor subunits expression in primary cortical neurons","volume":"69","author":"Chernova","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.bbrc.2010.05.011","article-title":"Senescence-associated beta-galactosidase activity expression in aging hippocampal neurons","volume":"396","author":"Geng","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/01.brs.0000253960.57051.de","article-title":"Senescence in cells of the aging and degenerating intervertebral disc: Immunolocalization of senescence-associated beta-galactosidase in human and sand rat discs","volume":"32","author":"Gruber","year":"2007","journal-title":"Spine"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s10517-021-05192-6","article-title":"Peptide KED: Molecular-Genetic Aspects of Neurogenesis Regulation in Alzheimer\u2019s Disease","volume":"171","author":"Khavinson","year":"2021","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Khavinson, V., Diomede, F., Mironova, E., Linkova, N., Trofimova, S., Trubiani, O., Caputi, S., and Sinjari, B. (2020). AEDG Peptide (Epitalon) Stimulates Gene Expression and Protein Synthesis during Neurogenesis: Possible Epigenetic Mechanism. Molecules, 25.","DOI":"10.3390\/molecules25030609"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eaal3024","DOI":"10.1126\/scisignal.aal3024","article-title":"Resveratrol stimulates the metabolic reprogramming of human CD4(+) T cells to enhance effector function","volume":"10","author":"Craveiro","year":"2017","journal-title":"Sci. Signal."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/9\/739\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:43:08Z","timestamp":1760035388000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/9\/739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cimb47090739"],"URL":"https:\/\/doi.org\/10.3390\/cimb47090739","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]}}}