Progress and Perspectives in Allogeneic Cell‐Based Pulp Regeneration

Background Cell‐based regenerative endodontic procedures (REPs) using dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs) and those from apical papillae have shown great potential for authentic pulp regeneration, as evidenced by reports from preclinical studies and limited clinical trials. However, challenges, such as low cell survival rates, immune rejection during allogeneic transplantation and inconsistent protocols, hinder their widespread clinical implementation. Objectives This review aimed to summarise the regenerative methodologies widely used in studies involving autologous and allogenic DPSC/SHED transplantation and their clinical outcomes, analyse the discrepancies between preclinical and clinical studies, explore the potential mechanisms underlying alloimmune responses in allogeneic cell transplantation and provide possible strategies to minimise this type of immune rejection. Methods A comprehensive search was conducted on clinicaltrials.gov using keywords ‘(dental pulp stem cells) OR (dental pulp mesenchymal cells) OR (DPSCs) OR (human deciduous teeth stem cells) OR (stem cells from human exfoliated teeth) OR (SHED),’ followed by inputting keywords ‘(NestaCell) OR (Cellavita HD).’ Clinical trials not registered on the website and case reports were also included via advanced search on PubMed using keywords ‘(dental pulp stem cells) OR (dental pulp mesenchymal cells) OR (DPSCs) OR (human deciduous teeth stem cells) OR (stem cells from human exfoliated teeth) OR (SHED)’ with filters ‘(Case reports) AND (Clinical trial).’ Results Twenty‐seven clinical trials and 11 case reports were included. Whereas these studies related to endodontic diseases revealed favourable outcomes for teeth treated with pulp regeneration approaches, preclinical studies observed limited cell survival in vivo, indicating that DPSCs exhibit environment‐dependent immunogenicity and immunoregulatory properties under favourable conditions but become immunogenic in stressful microenvironments such as cell passage and differentiation, hypoxia and inflammation. Potential strategies have been developed to prolong DPSC survival. Conclusions Despite encouraging preliminary results, significant limitations remain in the establishment of standardised protocols and the development of reliable techniques for longitudinal cell tracking. In future research, optimised delivery systems, immune‐evasive cell engineering and rigorous clinical trial designs should be optimised to advance REPs towards predictable, clinically viable therapies.