Bioinspired Microgel Assembly of Liver-Derived Decellularized Extracellular Matrix Enhances Dentin-Pulp Regeneration via Stemness Awakening.

Abstract

Gradual loss of cellular potency during in vitro expansion is a primary challenge in the clinical translation of stem cell therapies. This decline in regenerative potential significantly compromises regenerative endodontic therapy (RET)-an emerging strategy for reconstructing dentin-pulp complex. Hence, we develop an injectable microgel scaffold composed of porcine liver-derived decellularized extracellular matrix (dECM) and gelatin methacryloyl (GelMA). This system, which is designated as a high-concentration dECM/GelMA assembled microgel scaffold (HdG-AMS), integrates the bioactivity of dECM with the structural stability of GelMA to reconstitute a native-like stem cell niche. The HdG-AMS creates a robust biomimetic niche that effectively restores dental pulp stem cell (DPSC) stemness while simultaneously activating the odontogenic and angiogenic pathways. Through RNA sequencing, we mechanistically identify that the HdG-AMS counteracts cellular senescence by upregulating FOXM1-a pivotal activator of the Wnt/β-catenin signaling pathway. Functional validation in two animal models demonstrate effective dentin-bridge formation in direct pulp capping therapy and the regeneration of vascularized dentin-pulp complex upon subcutaneous transplantation. Collectively, the HdG-AMS functions as a bioinspired signaling niche that awakens DPSC stemness and orchestrates dentin formation and vascularization via FOXM1/Wnt/β-catenin axis, thus offering a translational scaffold for next-generation RET.