Mesenchymal stem cell-based therapy is a reliable treatment for periodontal tissue regeneration, while ideal regeneration rate is still a facing problem. In previous study, we found SFRP2 a promising gene in modulating mesenchymal stem cells potential. We further investigated its role on periodontal tissue regeneration.We created periodontitis model in miniature pigs and locally injected with stem cells from apical papilla (SCAP). The periodontitis models were classed into three groups, SFRP2-SCAP group (injected with SCAP overexpressing with SFRP2), SCAP group (injected with SCAP transduced with vector backbone) and saline group (vehicle group injected with saline). Clinical assignment, CT scanning, histopathological assessment and quantitative analysis were applied to evaluate the regeneration effect.12 weeks after the injection, we found healthier gingival status in SFRP2-SCAP group than the other two groups. Clinical assignments results showed values of probing depth, gingival recession, and attachment loss were improved in SFRP2-SCAP group than that of SCAP group and saline group. The volume of new born bone was also enhanced in SFRP2-SCAP group than SCAP group and saline group. The difference of clinical assignments and new born bone between each group were significant relevant. HE staining demonstrated increased tissue regeneration in SFRP2-SCAP group than SCAP group and saline group.Our findings revealed that SFRP2 could enhance SCAP mediated periodontal tissue regeneration and provide a potential target for improving the regeneration of periodontal tissue. This article is protected by copyright. All rights reserved.