“Young-Mechanical Niche” biomimetic hydrogel promotes dental pulp regeneration through YAP-dependent mechanotransduction

Aging leads to the irreversible deterioration of the extracellular matrix (ECM), compromising cell self-renewal, differentiation, and tissue regeneration. However, the specific mechanisms by which age-related changes in ECM-mediated cell mechanical microenvironment impair regeneration remain elusive. Human dental pulps (hDPs) provide an ideal model to explore this issue due to their accessibility and distinct mechanical properties. In this study, we discovered that young hDPs exhibit higher stiffness and viscoelasticity (i.e., faster stress relaxation time) compared to aged hDPs. Leveraging these findings, we engineered three groups of biomimetic hydrogels recapitulating the native mechanical microenvironment of young and aged hDPs. Our results demonstrated that Y-Gel, which replicates the high stiffness and viscoelasticity of young hDPs, significantly enhances the proliferation and odontogenic differentiation of human dental pulp stem cells (hDPSCs) in vitro and promotes dental pulp regeneration in vivo more effectively than hydrogels mimicking either aged stiffness (AS-Gel) or aged viscoelasticity (AV-Gel) alone. Moreover, YAP-dependent mechanotransduction, particularly through the YAP/TEAD1/CTGF/Cyr61 signaling pathway, plays a critical role in mediating these regenerative effects, with stiffness emerging as a more dominant factor than viscoelasticity. This study provides new insights into the synergistic role of mechanical factors in regulating cell behavior and offers a promising strategy for optimizing mechanical microenvironment to enhance dental pulp regeneration and potentially other tissue regeneration applications, especially from the mechanomedicine perspective.