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The condition of the periodontal ligament (PDL) is a prognostic factor that affects replantation outcomes. Various studies have been devoted to improving the repair of the PDL after replantation to improve the prognosis. Prostaglandin E2 (PGE2), an inflammatory mediator with critical effects involved in stem cell regulation as well as in tissue repair and regeneration, has been found to be increased after replantation. Thus, we hypothesized that the increased PGE2 in the PDL microenvironment may influence the viability of the PDL stem cells to affect PDL repair and improve replantation outcomes. We established a mouse model and found increased cyclooxygenase-2 expression and PGE2 concentrations within 1 to 3 d postreplantation. Human PDL stem cells (hPDLSCs) were stimulated with PGE2 and an EP4 agonist (L-902688) to assess viability, apoptosis, and cell cycle. Ribonucleic acid sequencing was performed to explore downstream mechanisms. The reanalysis of single-cell ribonucleic acid sequencing data suggested EP4 was the principal effective PGE2 receptor. PGE2 and EP4 agonist treatment enhanced the proliferation and viability of hPDLSCs. Ribonucleic acid sequencing identified transcriptional and immune response regulator (TCIM), a positive regulator of the Wnt\/\u03b2-catenin signaling pathway, as a key downstream target. Knockdown of TCIM abrogated the proliferative effects of PGE2. In a mouse intervention model, the administration of SW033291 (a 15-hydroxyprostaglandin dehydrogenase inhibitor) or L-902688 significantly improved outcomes and increased TCIM expression in vivo. Our study demonstrates that PGE2 transiently increases in the PDL following replantation and enhances the proliferative capacity of hPDLSCs via EP4 activation, leading to the upregulation of TCIM and Wnt pathway activation. These findings offer mechanistic insight into periodontal repair and support the development of pharmaceutical strategies to improve replantation outcomes.<\/jats:p>","DOI":"10.1177\/00220345251407594","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T04:21:14Z","timestamp":1770870074000},"page":"1205-1214","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["PGE2 Regulates Periodontal Ligament Repair after Tooth Replantation"],"prefix":"10.1177","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3221-7891","authenticated-orcid":false,"given":"Y.","family":"Zhang","sequence":"first","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6912-1623","authenticated-orcid":false,"given":"W.","family":"Wu","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2218-7694","authenticated-orcid":false,"given":"J.","family":"Sun","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3305-1434","authenticated-orcid":false,"given":"X.","family":"Chen","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3260-3129","authenticated-orcid":false,"given":"J.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8247-7387","authenticated-orcid":false,"given":"Z.","family":"Chen","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"crossref","unstructured":"Bensman A. 2019. 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