{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:52:04Z","timestamp":1787014324175,"version":"build-2736575974"},"reference-count":69,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470937"],"award-info":[{"award-number":["82470937"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82401052"],"award-info":[{"award-number":["82401052"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int Endodontic J"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>The stem\/progenitor cell is crucial for organogenesis. Sensory nerves, as key components of the stem cell niche, secrete various factors to modulate stem\/progenitor cell fate decision. Here, we utilised tooth root development as a model to explore the role of sensory nerves in this regulatory process and to elucidate the underlying mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>\n                      Spatiotemporal dynamics of nerve innervation were characterised during tooth root development. We treated mouse dental papilla cells (mDPCs) with trigeminal ganglion\u2010conditioned medium (TG\u2010CM) and employed a subrenal co\u2010culture of TG\u2010tooth germ to evaluate sensory nerve function in odontoblastic differentiation and tooth root formation. A subrenal co\u2010culture of TG\u2010tooth germ was employed to detect sensory nerve function in tooth root formation. Integrated analysis of scRNA\u2010seq from the TG and molar at post\u2010natal day 3.5 (PN3.5) and PN30 identified potential nerve\u2010derived factors, which were further assessed through subrenal transplantation with recombinant protein\u2010loaded or neutralising antibody\u2010loaded beads. CellChat was used to analyse cell\u2013cell communication between TGs and molars. Co\u2010immunoprecipitation (Co\u2010IP) and proximity ligation assays (PLA) were used to confirm the interaction between secreted phosphoprotein 1 (SPP1) and integrin alpha 4 (ITGA4). The siRNA\u2010mediated\n                      <jats:italic>Itga4<\/jats:italic>\n                      knockdown assessed its role in odontoblastic differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sensory nerve fibres localized to the apical papilla and follicle at PN3.5 and extended toward the crown. TG\u2010CM and subrenal co\u2010culture of TG\u2010tooth germ enhanced odontoblast differentiation and root elongation, demonstrating the indispensable role of sensory nerves for proper root development. Integrated scRNA\u2010seq analysis of TG and molar at PN3.5 and PN30 uncovered various sensory nerve\u2010derived factors, including SPP1, calcitonin gene\u2010related polypeptide (CGRP) and kit ligand (KITL), whose function in tooth root development was validated in\u00a0vivo. Furthermore, CellChat analysis revealed SPP1\u2010ITGA4 as a critical ligand\u2010receptor interaction, which was confirmed by Co\u2010IP and PLA.\n                      <jats:italic>Itga4<\/jats:italic>\n                      was specifically expressed in the apical papilla and upregulated during odontoblastic differentiation.\n                      <jats:italic>Itga4<\/jats:italic>\n                      knockdown impaired odontoblastic differentiation and abolished SPP1\u2010promoted odontogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, our findings elucidate a novel mechanism whereby sensory nerves orchestrate tooth root development by regulating progenitor cell fate through the SPP1\/ITGA4 axis. This neuro\u2010mesenchymal crosstalk provides insights for stem cell therapies and tooth root regeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iej.70129","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:59:54Z","timestamp":1773032394000},"page":"1451-1464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sensory Nerves Regulate Odontoblast Differentiation via the SPP1\/ITGA4 Axis During Tooth Root Development"],"prefix":"10.1111","volume":"59","author":[{"given":"Huanyan","family":"Zuo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"},{"name":"Center for Cariology, Endodontics and Periodontics, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjie","family":"Shuai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diduo","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7949-4511","authenticated-orcid":false,"given":"Fei","family":"Pei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan University  Wuhan China"},{"name":"Department of Cariology and Endodontics, School &amp; 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