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• HA degradation promotes odontoblastic differentiation and cell migration of mouse dental papilla cells. • During odontoblastic differentiation, HYAL2 is highly localized in odontoblasts in vivo. • Hyal2 knockdown leads to the accumulation of HA, which impedes dentinogenesis and cell migration. • Hyal2 silencing significantly affects the cytoskeletal networks and focal adhesion, and inhibits the activation of PI3K/Akt signaling pathway. The coordination between odontoblastic differentiation and directed cell migration of mesenchymal progenitors is necessary for regular dentin formation. The synthesis and degradation of hyaluronan (HA) in the extracellular matrix create a permissive niche that directly regulates cell behaviors. However, the role and mechanisms of HA degradation in dentin formation remain unknown. In this work, we present that HA digestion promotes odontoblastic differentiation and cell migration of mouse dental papilla cells (mDPCs). Hyaluronidase 2 (HYAL2) is responsible for promoting odontoblastic differentiation through degrading HA, while hyaluronidase 1 (HYAL1) exhibits negligible effect. Silencing Hyal2 generates an extracellular environment rich in HA, which attenuates F-actin and filopodium formation and in turn inhibits cell migration of mDPCs. In addition, activating PI3K/Akt signaling significantly rescues the effects of HA accumulation on cytodifferentiation. Taken together, the results confirm the contribution of HYAL2 to HA degradation in dentinogenesis and uncover the mechanism of the HYAL2-mediated HA degradation in regulating the odontoblastic differentiation and migration of mDPCs. [ABSTRACT FROM AUTHOR]