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Mechanistic studies revealed that DPP stimulation of DPSCs positively impacted the differentiation of DPSCs into functional odontoblasts. Results show that NF-\u03baB signaling and transcriptional activation of genes involved in odontoblast differentiation were influenced by DPP signaling. Specifically, RelA\/p65 subunit of NF-\u03baB was identified as being responsible for the initiation of the differentiation cascade. Confocal imaging demonstrated the nuclear translocation of p65 with DPP stimulation. Moreover, direct binding of nuclear NF-\u03baB p65 subunit to the promoter elements of Runx2, Osx, OCN, MMP1, MMP3, BMP4 and PTX3 were identified by ChIP analysis. Pharmacological inhibition of the NF-\u03baB pathway using TPCA-1, a selective inhibitor of IKK-2 and JSH-23, an inhibitor that prevents nuclear translocation and DNA binding of p65 showed impairment in the differentiation process. Functional studies using Alizarin-Red staining showed robust mineral deposits with DPP stimulation and sparse deposition with defective odontoblast differentiation in the presence of inhibitors. In vivo expression of NF-\u03baB targets such as OSX, OCN, PTX3 and p65 in odontoblasts and dental pulp cells from DSPP null mouse was lower when compared with the wild-type. Overall, the results suggest an important role for DPP-mediated NF-\u03baB activation in the transcriptional regulation of early odontogenic markers that promote differentiation of DPSCs.<\/jats:p>","DOI":"10.1038\/s41598-021-01359-3","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T11:06:09Z","timestamp":1636628769000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["DPP promotes odontogenic differentiation of DPSCs through NF-\u03baB signaling"],"prefix":"10.1038","volume":"11","author":[{"given":"Yinghua","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrienn","family":"Peth\u00f6","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amudha","family":"Ganapathy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"George","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"1359_CR1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345211018405","author":"J Moradian-Oldak","year":"2021","unstructured":"Moradian-Oldak, J. & George, A. 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