{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:33:28Z","timestamp":1783384408916,"version":"3.54.6"},"reference-count":58,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Olfactory impairment is one of the most common diseases of the sense organs, and it is closely related to quality life. Although the molecular mechanism of olfaction was recently brought to light, the pathophysiology and effective treatments for olfactory dysfunction still remain challenging. Olfactory impairment can be caused by the degeneration of olfactory receptor neurons in the nose and also by the degeneration of the olfactory bulb of the olfactory cortex. Several studies have shown that stem cells promote the regeneration of the olfactory neuroepithelium after permanent damage in anosmic mice. Transplanted adipose stem cells differentiated into olfactory receptor neurons and endothelial cells. Recently, cell-free approaches using stem cell-derived secretome and extracellular vesicles (EVs) have emerged as a safer, more controllable alternative. These vesicles contain biologically active cargo such as neurotrophins, cytokines, and microRNAs that promote neurogenesis and modulate inflammation. Although direct application in anosmia models remains limited, findings from related neural injury models suggest that secretome- and EV-based therapies may achieve comparable regenerative efficacy to stem cell transplantation. This review summarizes current evidence on the regenerative capacity of stem cells and their secretome or EVs as therapeutic strategies for olfactory epithelium regeneration.<\/jats:p>","DOI":"10.3390\/ijms26189024","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T05:59:51Z","timestamp":1758088791000},"page":"9024","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Stem Cells and Cell-Free Therapies for Olfactory Epithelium Regeneration: Insights from Experimental Models"],"prefix":"10.3390","volume":"26","author":[{"given":"Keun-Ik","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9301-6957","authenticated-orcid":false,"given":"Ji-Hwan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Dong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan 49241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4486-7178","authenticated-orcid":false,"given":"Sue Jean","family":"Mun","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu-Sup","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan 49241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"891","DOI":"10.2174\/1570159X17666181206095626","article-title":"Sense of smell: Structural, functional, mechanistic advancements and challenges in human olfactory research","volume":"17","author":"Sharma","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s00441-020-03367-7","article-title":"The importance of olfactory system in human well-being, through nutrition and social behavior","volume":"383","author":"Boesveldt","year":"2021","journal-title":"Cell Tissue Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jaip.2020.10.036","article-title":"The importance of considering olfactory dysfunction during the COVID-19 pandemic and in clinical practice","volume":"9","author":"Desai","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s00441-020-03381-9","article-title":"Human olfactory dysfunction: Causes and consequences","volume":"383","author":"Schriever","year":"2021","journal-title":"Cell Tissue Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"208","DOI":"10.3389\/fnagi.2020.00208","article-title":"Age-related olfactory dysfunction: Epidemiology, pathophysiology, and clinical management","volume":"12","author":"Kondo","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11882-022-01028-z","article-title":"Therapies for olfactory dysfunction\u2014An update","volume":"22","author":"Jafari","year":"2022","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3389\/fnins.2014.00182","article-title":"A lifetime of neurogenesis in the olfactory system","volume":"8","author":"Brann","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Liang, F. (2020). Sustentacular cell enwrapment of olfactory receptor neuronal dendrites: An update. Genes, 11.","DOI":"10.3390\/genes11050493"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1406218","DOI":"10.3389\/fncir.2024.1406218","article-title":"Structures and functions of the normal and injured human olfactory epithelium","volume":"18","author":"Kikuta","year":"2024","journal-title":"Front. Neural Circuits"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"76","DOI":"10.18787\/jr.2025.00013","article-title":"Stem cell niches for olfactory regeneration and their therapeutic applications","volume":"32","author":"Kang","year":"2025","journal-title":"J. Rhinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"dev201552","DOI":"10.1242\/dev.201552","article-title":"Horizontal basal cells self-govern their neurogenic potential during injury-induced regeneration of the olfactory epithelium","volume":"150","author":"Louie","year":"2023","journal-title":"Development"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"602688","DOI":"10.3389\/fnagi.2020.602688","article-title":"Age-dependent activation and neuronal differentiation of Lgr5+ basal cells in injured olfactory epithelium via notch signaling pathway","volume":"12","author":"Li","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0155167","DOI":"10.1371\/journal.pone.0155167","article-title":"Sox2 and Pax6 play counteracting roles in regulating neurogenesis within the murine olfactory epithelium","volume":"11","author":"Packard","year":"2016","journal-title":"PLoS ONE"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2640","DOI":"10.1371\/journal.pone.0002640","article-title":"Principles of glomerular organization in the human olfactory bulb\u2014implications for odor processing","volume":"3","author":"Maresh","year":"2008","journal-title":"PLoS ONE"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"752320","DOI":"10.3389\/fnsys.2021.752320","article-title":"Human primary olfactory amygdala subregions form distinct functional networks, suggesting distinct olfactory functions","volume":"15","author":"Noto","year":"2021","journal-title":"Front. Syst. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.3389\/fpsyg.2013.01011","article-title":"The olfactory system as the gateway to the neural correlates of consciousness","volume":"4","author":"Merrick","year":"2014","journal-title":"Front. Psychol."},{"key":"ref_17","first-page":"379","article-title":"Methimazole-induced damage in the olfactory mucosa: Effects on ultrastructure and glutathione levels","volume":"31","author":"Giovanetti","year":"2003","journal-title":"Toxicol. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/jnr.21155","article-title":"Methimazole-induced cell death in rat olfactory receptor neurons occurs via apoptosis triggered through mitochondrial cytochrome c-mediated caspase-3 activation pathway","volume":"85","author":"Sakamoto","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1093\/chemse\/bjg053","article-title":"Does intranasal application of zinc sulfate produce anosmia in the mouse? An olfactometric and anatomical study","volume":"28","author":"McBride","year":"2003","journal-title":"Chem. Senses"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.taap.2013.07.020","article-title":"Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: Effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6","volume":"272","author":"Xie","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e81-4","DOI":"10.2500\/ajra.2012.26.3719","article-title":"Effects of statins on the recovery of olfactory function in a 3-methylindole-induced anosmia mouse model","volume":"26","author":"Kim","year":"2012","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"113548","DOI":"10.1016\/j.physbeh.2021.113548","article-title":"The olfactory bulbectomy disease model: A re-evaluation","volume":"240","author":"Coppola","year":"2021","journal-title":"Physiol. Behav."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/glia.440030104","article-title":"Transection of the rat olfactory nerve increases glial fibrillary acidic protein immunoreactivity from the olfactory bulb to the piriform cortex","volume":"3","author":"Anders","year":"1990","journal-title":"Glia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0006-8993(79)90069-6","article-title":"Cell suspensions from rat olfactory neuroepithelium: Biochemical and histochemical characterization","volume":"161","author":"Hirsch","year":"1979","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1177\/194589240501900302","article-title":"Development of transgenic mouse models for the study of human olfactory dysfunction","volume":"19","author":"Lane","year":"2005","journal-title":"Am. J. Rhinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"147","DOI":"10.5625\/lar.2018.34.4.147","article-title":"Mouse Cre-LoxP system: General principles to determine tissue-specific roles of target genes","volume":"34","author":"Kim","year":"2018","journal-title":"Lab. Anim. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00405-007-0487-6","article-title":"Maintenance of regional difference in cellular composition of neurospheres derived from adult mouse olfactory bulb","volume":"265","author":"Ahn","year":"2008","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1111\/jnc.15197","article-title":"Viral infection and smell loss: The case of COVID-19","volume":"157","author":"Glezer","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41421-021-00290-1","article-title":"SARS-CoV-2 infection in the mouse olfactory system","volume":"7","author":"Ye","year":"2021","journal-title":"Cell Discov."},{"key":"ref_30","first-page":"5275","article-title":"Establishment of a mouse model of lipopolysaccharide-induced neutrophilic nasal polyps","volume":"14","author":"Wang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6631857","DOI":"10.1155\/sci\/6631857","article-title":"Role and mechanism of olfactory stem cells in the treatment of olfactory disorders","volume":"2025","author":"Gan","year":"2025","journal-title":"Stem Cells Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8268","DOI":"10.1523\/JNEUROSCI.0240-14.2014","article-title":"Wnt-responsive Lgr5+ globose basal cells function as multipotent olfactory epithelium progenitor cells","volume":"34","author":"Chen","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E5068-77","DOI":"10.1073\/pnas.1512272112","article-title":"Transcription factor p63 controls the reserve status but not the stemness of horizontal basal cells in the olfactory epithelium","volume":"112","author":"Schnittke","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1002\/cne.24105","article-title":"Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license","volume":"525","author":"Schwob","year":"2017","journal-title":"J. Comp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.stem.2017.10.014","article-title":"Injury activates transient olfactory stem cell states with diverse lineage capacities","volume":"21","author":"Gadye","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1002\/stem.2837","article-title":"Notch signaling regulates Lgr5+ olfactory epithelium progenitor\/stem cell turnover and mediates recovery of lesioned olfactory epithelium in mouse model","volume":"36","author":"Dai","year":"2018","journal-title":"Stem Cells"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ramakrishna, K., Nalla, L.V., Naresh, D., Venkateswarlu, K., Viswanadh, M.K., Nalluri, B.N., Chakravarthy, G., Duguluri, S., Singh, P., and Rai, S.N. (2023). WNT-\u03b2 catenin signaling as a potential therapeutic target for neurodegenerative diseases: Current status and future perspective. Diseases, 11.","DOI":"10.3390\/diseases11030089"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"103913","DOI":"10.1016\/j.mcn.2023.103913","article-title":"Suppression of BMP signaling restores mitral cell development impaired by FGF signaling deficits in mouse olfactory bulb","volume":"128","author":"Ito","year":"2024","journal-title":"Mol. Cell Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nrendo.2014.208","article-title":"Insulin and IGF receptor signaling in neural-stem cell homeostasis","volume":"11","author":"Ziegler","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1021\/acschemneuro.0c00249","article-title":"Proinflammatory cytokines in the olfactory mucosa result in COVID-19 induced anosmia","volume":"11","author":"Torabi","year":"2022","journal-title":"ACS Chem. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1186\/s12964-023-01252-8","article-title":"Extracellular matrix-induced signaling pathways in mesenchymal stem\/stromal cells","volume":"21","author":"Novoseletskaya","year":"2023","journal-title":"Cell Commun. Signal"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kim, S.D., and Cho, K.S. (2022). Immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in allergic airway disease. Life, 12.","DOI":"10.3390\/life12121994"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/ar614","article-title":"Adult mesenchymal stem cells and cell-based tissue engineering","volume":"5","author":"Tuan","year":"2003","journal-title":"Arthritis Res. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/nri2395","article-title":"Mesenchymal stem cells in health and disease","volume":"8","author":"Uccelli","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1002\/lary.20187","article-title":"Effects of systemic transplantation of adipose tissue-derived stem cells on olfactory epithelium regeneration","volume":"119","author":"Kim","year":"2009","journal-title":"Laryngoscope"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1002\/stem.11","article-title":"Human cord blood CD133+ stem cells transplanted to nod-scid mice provide conditions for regeneration of olfactory neuroepithelium after permanent damage induced by dichlobenil","volume":"27","author":"Franceschini","year":"2009","journal-title":"Stem Cells"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"84","DOI":"10.3342\/ceo.2010.3.2.84","article-title":"Transplantation of neural stem cells in anosmic mice","volume":"3","author":"Lee","year":"2010","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.bbrc.2015.09.142","article-title":"The effect of rat bone marrow derived mesenchymal stem cells transplantation for restoration of olfactory disorder","volume":"467","author":"Jo","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"17015","DOI":"10.1038\/s41598-025-01358-8","article-title":"Effect of intranasal neural stem cells transplantation on olfactory epithelium regeneration in an anosmia-induced mouse model","volume":"15","author":"Hazir","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1517\/14712598.2016.1131976","article-title":"Exosomes for repair, regeneration and rejuvenation","volume":"16","author":"Basu","year":"2016","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41392-024-01735-1","article-title":"Extracellular vesicles as tools and targets in therapy for diseases","volume":"9","author":"Kumar","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1002\/stem.1409","article-title":"MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles","volume":"31","author":"Xin","year":"2013","journal-title":"Stem Cells"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6686625","DOI":"10.1155\/2021\/6686625","article-title":"Intranasally administrated extracellular vesicles from adipose stem cells have immunomodulatory effects in a mouse model of asthma","volume":"2021","author":"Mun","year":"2021","journal-title":"Stem Cells Int."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Jung, J.H., Kang, S.A., Park, J.H., Kim, S.D., Yu, H.S., Mun, S.J., and Cho, K.S. (2024). Immunomodulatory effect of adipose stem cell-derived extra-cellular vesicles on cytokine expression and regulatory T cells in patients with asthma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910524"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Jung, J.H., Kang, S.A., Park, J.H., Kim, S.D., Yu, H.S., Mun, S.J., and Cho, K.S. (2024). Paraoxonase-1 is a pivotal regulator responsible for suppressing allergic airway inflammation through adipose stem cell-derived extracellular vesicles. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312756"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Yavuz, B., Mutlu, E.C., Ahmed, Z., Ben-Nissan, B., and Stamboulis, A. (2024). Applications of stem cell-derived extracellular vesicles in nerve regeneration. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115863"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Alvites, R.D., Branquinho, M.V., Sousa, A.C., Lopes, B., Sousa, P., Prada, J., Pires, I., Ronchi, G., Raimondo, S., and Lu\u00eds, A.L. (2022). Effects of olfactory mucosa stem\/stromal cell and olfactory ensheating cells secretome on peripheral nerve regeneration. Biomolecules, 12.","DOI":"10.20944\/preprints202204.0274.v1"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9024\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:40Z","timestamp":1760035600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":58,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26189024"],"URL":"https:\/\/doi.org\/10.3390\/ijms26189024","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,16]]}}}