Direct transplantation of multipotent precursor cells into the periodontium could provide a therapeutic approach for restoring periodontal tissues destroyed by periodontitis or trauma. To improve the understanding of cell migration, proliferation, and differentiation, we used a rodent model combining orthodontic tooth movement and transplantation of Lac-Z-positive murine-cultured periodontal ligament (PL) or femur-derived bone marrow precursor cells into a defined mandibular wound site, thus promoting tissue regeneration in wounded periodontium. Our results show that in orthodontically traumatized tissues, transplanted PL and bone marrow cells migrated systemically, contributing to the repopulation of sites with reduced cell/matrix density. The transplanted PL cells proliferated in adjacent alveolar bone marrow spaces, thus migrating to vascular tissues in the PL. The capillary walls in the PL serve as delivery sites for these cells and other marrow-derived hematopoietic cells, including monocytes. The transplanted marrow cells, extracted from femur of transgenic (TgR) mice exhibited similar behavior to those of transplanted PL cells, showing high proliferative activity in alveolar marrow as well as intensive repopulating capacity in wounded periodontium. On the other hand, the buccal skin fibroblasts failed to migrate and home effectively and thus the transplantation of these cells had no effect on periodontium regeneration. Based on these results, we conclude that the transplanted PL and bone marrow cells migrate systemically and following a cyclical process of growth and development and differentiate into PL fibroblasts, osteoblasts, and cementoblasts, thereby contributing to periodontal regeneration. © 2005 Wiley-Liss, Inc.