{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T11:51:02Z","timestamp":1783597862826,"version":"3.55.0"},"reference-count":43,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIDCR","award":["R01 DE029816 (SC)"],"award-info":[{"award-number":["R01 DE029816 (SC)"]}]},{"name":"NIDCR","award":["R01 DE031737 (AG)"],"award-info":[{"award-number":["R01 DE031737 (AG)"]}]},{"name":"NIDCR","award":["R01 DE028531 (AG)"],"award-info":[{"award-number":["R01 DE028531 (AG)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The odontoblastic differentiation of dental pulp stem cells (DPSCs) associated with caries injury happens in an inflammatory context. We recently demonstrated that there is a link between inflammation and dental tissue regeneration, identified via enhanced DPSC-mediated dentinogenesis in vitro. Brain-derived neurotrophic factor (BDNF) is a nerve growth factor-related gene family molecule which functions through tropomyosin receptor kinase B (TrkB). While the roles of BDNF in neural tissue repair and other regeneration processes are well identified, its role in dentinogenesis has not been explored. Furthermore, the role of BDNF receptor-TrkB in inflammation-induced dentinogenesis remains unknown. The role of BDNF\/TrkB was examined during a 17-day odontogenic differentiation of DPSCs. Human DPSCs were subjected to odontogenic differentiation in dentinogenic media treated with inflammation inducers (LTA or TNF\u03b1), BDNF, and a TrkB agonist (LM22A-4) and\/or antagonist (CTX-B). Our data show that BDNF and TrkB receptors affect the early and late stages of the odontogenic differentiation of DPSCs. Immunofluorescent data confirmed the expression of BDNF and TrkB in DPSCs. Our ELISA and qPCR data demonstrate that TrkB agonist treatment increased the expression of dentin matrix protein-1 (DMP-1) during early DPSC odontoblastic differentiation. Coherently, the expression levels of runt-related transcription factor 2 (RUNX-2) and osteocalcin (OCN) were increased. TNF\u03b1, which is responsible for a diverse range of inflammation signaling, increased the levels of expression of dentin sialophosphoprotein (DSPP) and DMP1. Furthermore, BDNF significantly potentiated its effect. The application of CTX-B reversed this effect, suggesting TrkB`s critical role in TNF\u03b1-mediated dentinogenesis. Our studies provide novel findings on the role of BDNF-TrkB in the inflammation-induced odontoblastic differentiation of DPSCs. This finding will address a novel regulatory pathway and a therapeutic approach in dentin tissue engineering using DPSCs.<\/jats:p>","DOI":"10.3390\/cells12141851","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T08:35:47Z","timestamp":1689323747000},"page":"1851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["BDNF\/TrkB Is a Crucial Regulator in the Inflammation-Mediated Odontoblastic Differentiation of Dental Pulp Stem Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Ji-Hyun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9788-8231","authenticated-orcid":false,"given":"Muhammad","family":"Irfan","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Akil","family":"Hossain","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"George","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1449-8762","authenticated-orcid":false,"given":"Seung","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"230251","DOI":"10.1155\/2015\/230251","article-title":"Dental Pulp Defence and Repair Mechanisms in Dental Caries","volume":"2015","author":"Farges","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Galler, K.M., Weber, M., Korkmaz, Y., Widbiller, M., and Feuerer, M. (2021). Inflammatory Response Mechanisms of the Dentine-Pulp Complex and the Periapical Tissues. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031480"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1177\/154411130201300207","article-title":"Invasion of Dentinal Tubules by Oral Bacteria","volume":"13","author":"Love","year":"2002","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1111\/iej.12906","article-title":"Disclosing the Physiology of Pulp Tissue for Vital Pulp Therapy","volume":"51","author":"Piva","year":"2018","journal-title":"Int. Endod. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0030-4220(90)90333-N","article-title":"Healing of Primate Dental Pulps Capped with Teflon","volume":"69","author":"Heys","year":"1990","journal-title":"Oral Surg. Oral Med. Oral Pathol."},{"key":"ref_6","first-page":"33","article-title":"Dental Pulp Stem Cells: Advances to Applications","volume":"13","author":"Tsutsui","year":"2020","journal-title":"Stem Cells Cloning Adv. Appl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13625","DOI":"10.1073\/pnas.240309797","article-title":"Postnatal Human Dental Pulp Stem Cells (DPSCs) in Vitro and in Vivo","volume":"97","author":"Gronthos","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Delle Monache, S., Pulcini, F., Frosini, R., Mattei, V., Talesa, V.N., and Antognelli, C. (2021). Methylglyoxal-Dependent Glycative Stress Is Prevented by the Natural Antioxidant Oleuropein in Human Dental Pulp Stem Cells through Nrf2\/Glo1 Pathway. Antioxidants, 10.","DOI":"10.3390\/antiox10050716"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Delle Monache, S., Pulcini, F., Santilli, F., Martellucci, S., Santacroce, C., Fabrizi, J., Angelucci, A., Sorice, M., and Mattei, V. (2022). Hypoxia Induces DPSC Differentiation versus a Neurogenic Phenotype by the Paracrine Mechanism. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051056"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nature13536","article-title":"Glial Origin of Mesenchymal Stem Cells in a Tooth Model System","volume":"513","author":"Kaukua","year":"2014","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1080\/19336896.2018.1463797","article-title":"Role of Prion Protein-EGFR Multimolecular Complex during Neuronal Differentiation of Human Dental Pulp-Derived Stem Cells","volume":"12","author":"Martellucci","year":"2018","journal-title":"Prion"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3389\/fncel.2019.00363","article-title":"Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain","volume":"13","author":"Miranda","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"276","DOI":"10.2174\/157015909790031210","article-title":"A New Aspect of the TrkB Signaling Pathway in Neural Plasticity","volume":"7","author":"Ohira","year":"2009","journal-title":"Curr. Neuropharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"490","DOI":"10.3748\/wjg.v22.i2.490","article-title":"Tropomyosin-Related Kinase B\/Brain Derived-Neurotrophic Factor Signaling Pathway as a Potential Therapeutic Target for Colorectal Cancer","volume":"22","author":"Akil","year":"2016","journal-title":"WJG"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1196\/annals.1366.012","article-title":"Roles of Glia-Derived Cytokines on Neuronal Degeneration and Regeneration","volume":"1088","author":"Suzumura","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1177\/0022034509334070","article-title":"TNF-\u03b1 Promotes an Odontoblastic Phenotype in Dental Pulp Cells","volume":"88","author":"Ghosh","year":"2009","journal-title":"J. Dent. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Jang, D., Lee, A.-H., Shin, H.-Y., Song, H.-R., Park, J.-H., Kang, T.-B., Lee, S.-R., and Yang, S.-H. (2021). The Role of Tumor Necrosis Factor Alpha (TNF-\u03b1) in Autoimmune Disease and Current TNF-\u03b1 Inhibitors in Therapeutics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052719"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.3389\/fphys.2018.01629","article-title":"Trophic Factors in Inflammation and Regeneration: The Role of MANF and CDNF","volume":"9","author":"Jasper","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41368-021-00140-6","article-title":"Single-Cell Characterization of Monolayer Cultured Human Dental Pulp Stem Cells with Enhanced Differentiation Capacity","volume":"13","author":"Cui","year":"2021","journal-title":"Int. J. Oral Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41368-022-00158-4","article-title":"The Role of Complement C5a Receptor in DPSC Odontoblastic Differentiation and in Vivo Reparative Dentin Formation","volume":"14","author":"Irfan","year":"2022","journal-title":"Int. J. Oral Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kim, J.-H., Irfan, M., Hossain, M.A., Shin, S., George, A., and Chung, S. (2023). LPS-Induced Inflammation Potentiates Dental Pulp Stem Cell Odontogenic Differentiation through C5aR and P38. Connect. Tissue Res., 1\u201311.","DOI":"10.1080\/03008207.2023.2218944"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Al-Maswary, A.A., O\u2019Reilly, M., Holmes, A.P., Walmsley, A.D., Cooper, P.R., and Scheven, B.A. (2022). Exploring the Neurogenic Differentiation of Human Dental Pulp Stem Cells. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0277134"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"G328","DOI":"10.1152\/ajpgi.00203.2013","article-title":"Brain-Derived Neurotrophic Factor Enhances Cholinergic Contraction of Longitudinal Muscle of Rabbit Intestine via Activation of Phospholipase C","volume":"306","author":"Anderson","year":"2014","journal-title":"Am. J. Physiol. -Gastrointest. Liver Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cazorla, M., Jouvenceau, A., Rose, C., Guilloux, J.-P., Pilon, C., Dranovsky, A., and Pr\u00e9mont, J. (2010). Cyclotraxin-B, the First Highly Potent and Selective TrkB Inhibitor, Has Anxiolytic Properties in Mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009777"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"119471","DOI":"10.1016\/j.lfs.2021.119471","article-title":"Artemisinin Protects DPSC from Hypoxia and TNF-\u03b1 Mediated Osteogenesis Impairments through CA9 and Wnt Signaling Pathway","volume":"277","author":"Hu","year":"2021","journal-title":"Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1177\/0022034516673832","article-title":"C5L2 Receptor Represses Brain-Derived Neurotrophic Factor Secretion in Lipoteichoic Acid-Stimulated Pulp Fibroblasts","volume":"96","author":"Chmilewsky","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1038\/s41598-022-06110-0","article-title":"Complement C5aR\/LPS-Induced BDNF and NGF Modulation in Human Dental Pulp Stem Cells","volume":"12","author":"Irfan","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1002\/jcp.24732","article-title":"LPS Promote the Odontoblastic Differentiation of Human Dental Pulp Stem Cells via MAPK Signaling Pathway: LPS promote the odontoblastic differentiation of hDPSCs","volume":"230","author":"He","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1007\/s11515-011-1123-9","article-title":"An Overview of Inflammation: Mechanism and Consequences","volume":"6","author":"Ahmed","year":"2011","journal-title":"Front. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1016\/j.ajpath.2014.04.003","article-title":"Pulp Fibroblasts Synthesize Functional Complement Proteins Involved in Initiating Dentin\u2013Pulp Regeneration","volume":"184","author":"Chmilewsky","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1016\/j.joen.2014.01.012","article-title":"Sources of Dentin-Pulp Regeneration Signals and Their Modulation by the Local Microenvironment","volume":"40","author":"Chmilewsky","year":"2014","journal-title":"J. Endod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.semcdb.2018.04.002","article-title":"Role of the Immune System in Regeneration and Its Dynamic Interplay with Adult Stem Cells","volume":"87","author":"Abnave","year":"2019","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/j.1600-0722.1998.tb02158.x","article-title":"NGF, BDNF, NT3, NT4 and GDNF in Tooth Development","volume":"106","author":"Nosrat","year":"1998","journal-title":"Eur. J. Oral Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lee, W.-D., Wang, K.-C., Tsai, Y.-F., Chou, P.-C., Tsai, L.-K., and Chien, C.-L. (2016). Subarachnoid Hemorrhage Promotes Proliferation, Differentiation, and Migration of Neural Stem Cells via BDNF Upregulation. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165460"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5139","DOI":"10.1523\/JNEUROSCI.1327-08.2008","article-title":"BDNF Signaling during Olfactory Bulb Neurogenesis","volume":"28","author":"Yuan","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/s10571-017-0510-4","article-title":"BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity","volume":"38","author":"Lietzau","year":"2018","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.5114\/aoms.2015.56342","article-title":"Brain-Derived Neurotrophic Factor and Its Clinical Implications","volume":"11","author":"Bathina","year":"2015","journal-title":"Arch. Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1210\/me.2012-1063","article-title":"BDNF Alters ERK\/P38 MAPK Activity Ratios to Promote Differentiation in Growth Plate Chondrocytes","volume":"26","author":"Hutchison","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1210\/me.2009-0228","article-title":"SCF, BDNF, and Gas6 Are Regulators of Growth Plate Chondrocyte Proliferation and Differentiation","volume":"24","author":"Hutchison","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1016\/j.joen.2014.01.021","article-title":"Inflammation and Regeneration in the Dentin-Pulp Complex: A Double-Edged Sword","volume":"40","author":"Cooper","year":"2014","journal-title":"J. Endod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20228","DOI":"10.1074\/jbc.M110.209528","article-title":"Expression of Phosphophoryn Is Sufficient for the Induction of Matrix Mineralization by Mammalian Cells","volume":"286","author":"Sfeir","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ydbio.2006.11.001","article-title":"Rescue of Odontogenesis in Dmp1-Deficient Mice by Targeted Re-Expression of DMP1 Reveals Roles for DMP1 in Early Odontogenesis and Dentin Apposition in Vivo","volume":"303","author":"Lu","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/j.archoralbio.2012.03.005","article-title":"Dentin Sialophosphoprotein and Dentin Matrix Protein-1: Two Highly Phosphorylated Proteins in Mineralized Tissues","volume":"57","author":"Suzuki","year":"2012","journal-title":"Arch. Oral Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/14\/1851\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:11:48Z","timestamp":1760127108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/14\/1851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,14]]},"references-count":43,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["cells12141851"],"URL":"https:\/\/doi.org\/10.3390\/cells12141851","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,14]]}}}