Hypoxia Promotes CEMP1 Expression and Induces Cementoblastic Differentiation of Human Dental Stem Cells in an HIF-1-Dependent Manner

Abstract

Cementum covering the tooth root provides attachment for the tooth proper to the surrounding alveolar bone via non-mineralized periodontal ligament (PDL). Cementum protein 1 (CEMP1) has been shown to induce a cementoblastic phenotype in cementoblast precursors cells of PDL. Oxygen availability is a critical signal for correct development of many tissues; however, its role in tooth root and periodontium development remains poorly understood. In this study, we demonstrated that reduced oxygen tension increased CEMP1 expression, mineral deposition, and alkaline phosphatase activity in human dental stem cells such as PDL stem cells and periapical follicular stem cells. Since an oxemic state is transduced by the transcription factor, hypoxia-inducible factor-1 (HIF-1), we performed experiments to determine whether this protein was responsible for the observed changes. We noted that when HIF-1 was activated by gene introduction or chemically, CEMP1 expression and mineralization increased. In contrast, when HIF-1α was silenced, CEMP1 expression and mineralization did not increase in vitro. Furthermore, we showed for the first time that mouse tooth root and periodontium development occurs partly under hypoxic conditions, particularly at the apical part and latently at the PDL space in vivo. Desferrioxamine, an HIF-1 stimulator, enhances CEMP1 expression in the mouse PDL space, suggesting that hypoxia affects cementogenesis of PDL cells lining the surface of the developing tooth root in an HIF-1-dependent manner. These results suggest that HIF-1 activators may have the ability to stimulate regeneration of the tooth root and cementum formation.