Mesenchymal stem cell-mediated functional tooth regeneration in swine is a promising approach for regenerative medicine. This study reports the use of stem cells isolated from the root apical papilla (SCAP) and periodontal ligament stem cells (PDLSCs) in a minipig model to regenerate a functional tooth. The transplanted cells formed a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This hybrid tissue engineering approach combined stem cell-mediated tissue regeneration, engineered materials, and current dental crown technologies to regenerate tooth strength and appearance. SCAP were isolated from human third molars and showed high expression of STRO-1 and other surface markers. They demonstrated the ability to differentiate into odontoblasts and adipocytes, and were capable of forming dentin and cementum in immunocompromised mice. SCAP were also found to have higher telomerase activity and proliferation rates compared to dental pulp stem cells (DPSCs), suggesting their potential for tissue regeneration. In the swine model, SCAP and PDLSCs were transplanted into a root-shaped HA/TCP block, which was then implanted into a socket after tooth extraction. A porcelain crown was affixed to the block, and after four weeks, the crown was retained in situ. CT and histologic analysis confirmed the regeneration of a root/periodontal structure, with the newly formed bio-roots showing improved compressive strength compared to the original HA/TCP carriers. This study demonstrates the feasibility of using autologous SCAP and PDLSCs in conjunction with artificial dental crowns for functional tooth regeneration. The results suggest that stem cell-mediated root regeneration combined with clinical crown technology may offer a promising approach for functional tooth restoration. The use of minipigs as a translational model for human tooth regeneration is supported by the close similarities between swine and human dental tissues. The study also highlights the potential of SCAP as a unique population of postnatal stem cells with advantages for tissue regeneration.Mesenchymal stem cell-mediated functional tooth regeneration in swine is a promising approach for regenerative medicine. This study reports the use of stem cells isolated from the root apical papilla (SCAP) and periodontal ligament stem cells (PDLSCs) in a minipig model to regenerate a functional tooth. The transplanted cells formed a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This hybrid tissue engineering approach combined stem cell-mediated tissue regeneration, engineered materials, and current dental crown technologies to regenerate tooth strength and appearance. SCAP were isolated from human third molars and showed high expression of STRO-1 and other surface markers. They demonstrated the ability to differentiate into odontoblasts and adipocytes, and were capable of forming dentin and cementum in immunocompromised mice. SCAP were also found to have higher telomerase activity and proliferation rates compared to dental pulp stem cells (DPSCs), suggesting their potential for tissue regeneration. In the swine model, SCAP and PDLSCs were transplanted into a root-shaped HA/TCP block, which was then implanted into a socket after tooth extraction. A porcelain crown was affixed to the block, and after four weeks, the crown was retained in situ. CT and histologic analysis confirmed the regeneration of a root/periodontal structure, with the newly formed bio-roots showing improved compressive strength compared to the original HA/TCP carriers. This study demonstrates the feasibility of using autologous SCAP and PDLSCs in conjunction with artificial dental crowns for functional tooth regeneration. The results suggest that stem cell-mediated root regeneration combined with clinical crown technology may offer a promising approach for functional tooth restoration. The use of minipigs as a translational model for human tooth regeneration is supported by the close similarities between swine and human dental tissues. The study also highlights the potential of SCAP as a unique population of postnatal stem cells with advantages for tissue regeneration.