{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T22:56:34Z","timestamp":1780527394012,"version":"3.54.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T00:00:00Z","timestamp":1705881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p><jats:bold>Background and Objectives:<\/jats:bold> Dental caries is one of the most common human pathological conditions resulting from the invasion of bacteria into the dentin. Current treatment options are limited. In many cases, endodontic therapy leads to permanent pulp tissue loss. Dentin\u2013pulp complex regeneration involves dental pulp stem cells (DPSCs) that differentiate into odontoblast-like cells under an inflammatory context. However, limited information is available on how DPSC differentiation processes are affected under inflammatory environments. We identified the crucial role of complement C5a and its receptor C5aR in the inflammation-induced odontoblastic DPSC differentiation.<\/jats:p><jats:p><jats:bold>Methodology:<\/jats:bold> Here, we further investigated the role of a second and controversial C5a receptor, C5L2, in this process and explored the underlying mechanism. Human DPSCs were examined during 7-, 10-, and 14-day odontogenic differentiation treated with TNF\u03b1, C5L2 CRISPR, and tyrosine receptor kinase B (TrkB) antagonist [cyclotraxin-B (CTX-B)].<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Our data demonstrate that C5L2 CRISPR knockout (KO) enhances mineralization in TNF\u03b1-stimulated differentiating DPSCs. We further confirmed that C5L2 CRISPR KO significantly enhances dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) expression after 14-day odontoblastic DPSC differentiation, and treatment with CTX-B abolished the TNF\u03b1\/C5L2 CRISPR KO-induced DSPP and DMP-1 increase, suggesting TrkB\u2019s critical role in this process.<\/jats:p><jats:p><jats:bold>Conclusion and Key applications:<\/jats:bold> Our data suggest a regulatory role of C5L2 and TrkB in the TNF\u03b1-induced odontogenic DPSC differentiation. This study may provide a useful tool to understand the mechanisms of the role of inflammation in dentinogenesis that is required for successful DPSC engineering strategies.<\/jats:p>","DOI":"10.3389\/fcell.2024.1338419","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T10:12:22Z","timestamp":1705918342000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["C5L2 CRISPR KO enhances dental pulp stem cell-mediated dentinogenesis via TrkB under TNF\u03b1-induced inflammation"],"prefix":"10.3389","volume":"12","author":[{"given":"Muhammad","family":"Irfan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Marzban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1002\/jcp.25940","article-title":"Stem cells applications in bone and tooth repair and regeneration: new insights, tools, and hopes","volume":"233","author":"Abdel Meguid","year":"2018","journal-title":"J. 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