Nociceptive Shh Promotes Lifelong Ctsk+ Dual Identities For Molar Odontogenesis

Preserving vital pulp represents both a central therapeutic objective and clinical challenge in tooth conservation across all life stages, with current limitations in insufficient characterization of lineage identities, neurogenic mechanism and endogenous reparative capacity. A reporter mouse line was developed with nuclear-localized GFP in Ctsk+ cells and followed by neonatal mouse molar single cell RNA sequencing investigation to validate lineage pattern. Mandibular denervation and Sonic Hedgehog (Shh) pathway inhibition model on genetic mice were established for dentin histological assessment and Ctsk+ lineage tracing to visualize neurogenic mechanism. Clinical injury models were simulated on genetic young and aged mice respectively, followed by direct Shh protein capping to trigger endogenous reparative capacity. Dual differentiation potential contributes to odontoblast commitment and label-retaining cell maintenance. Denervation disrupted Shh-dependent Ctsk+ progenitor recruitment during primary odontogenesis. Shh mediated two repair modalities: 1) physiological maintenance via paracrine signaling, and 2) enhanced reparative capacity through direct capping, expanding odontogenic potential of dual identities of Ctsk+ progenitors for both dentin development and aged molar injury repair. Ctsk-GFP expression exhibited odontogenic-phase specificity: retaining Ctsk+ odontoblasts and perivascular Ctsk+ progenitors with Shh-reactivable odontogenic competence. Neural integrity proved essential for physiological development and homeostasis from youth to aging. Nociceptive Shh mediated maintenance and enhanced reparative capacity for both young and aged odontogenesis. These findings position Shh-enhanced Ctsk+ lineage activation as a precision therapeutic strategy for vital pulp preservation across age groups, demonstrating targeted odontogenic potential restoration from developmental arrest to age-related degeneration.