Odontogenesis‐Empowered Extracellular Vesicles Safeguard Donor‐Recipient Stem Cell Interplay to Support Tooth Regeneration

Abstract Harnessing the developmental events of mesenchymal condensation to direct postnatal dental stem cell aggregation represents a cutting‐edge and promising approach to tooth regeneration. Tooth avulsion is among the most prevalent and serious dental injuries, and odontogenic aggregates assembled by stem cells from human exfoliated deciduous teeth (SHED) have proven effective in revitalizing avulsed teeth after replantation in the clinical trial. However, whether and how SHED aggregates (SA) communicate with recipient components and promote synergistic tissue regeneration to support replanted teeth remains elusive. Here, it is shown that SA‐mediated avulsed tooth regeneration involves periodontal restoration and recovery of recipient Gli1 ⁺ stem cells, which are mobilized and necessarily contribute to the reestablishment of the tooth‐periodontal ligament‐bone interface. Mechanistically, the release of extracellular vesicles (EVs) is revealed indispensable for the implanted SA to mobilize recipient Gli1 ⁺ cells and regenerate avulsed teeth. Furthermore, SHED aggregates‐released EVs (SA‐EVs) are featured with odontogenic properties linked to tissue regeneration, which enhance migration, proliferation, and differentiation of Gli1 ⁺ cells. Importantly, local application of SA‐EVs per se empowers recipient Gli1 ⁺ cells and safeguards regeneration of avulsed teeth. Collectively, the findings establish a paradigm in which odontogenesis‐featured EVs govern donor‐recipient stem cell interplay to achieve tooth regeneration, inspiring cell‐free translational regenerative strategies.