Undemineralized dentin matrix particles accelerate blood vessel formation in a critical-sized skull defect through activating the TGF-β/PI3K signaling pathway

Objective: To evaluate the effects of undemineralized dentin matrix (UDDM) particles on bone tissue regeneration and vascularization in a critical-sized skull defect (CSD) mouse model, and to elucidate the molecular mechanisms underlying UDDM extract-mediated promotion of endothelial cell proliferation, migration, and tube formation.

Methods: UDDM particles and extracts were sourced from human third molars. A CSD mouse model was established, and UDDM particles were implanted into the defect site. Bone regeneration and vascularization (blood vessel volume and area) were assessed using micro-computed tomography (Micro-CT). Human umbilical vein endothelial cells (HUVECs) were treated with UDDM extract and a phosphatidylinositol 3-kinase (PI3K) inhibitor (HY-15244). Cell proliferation, migration, and tube formation were assessed. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot were used to analyze the expression of transforming growth factor-beta (TGF-β)/PI3K signaling pathway-related genes and proteins.

Results: UDDM particles significantly enhanced bone formation and increased vascular volume and area in the CSD model. UDDM extract promoted HUVEC proliferation, migration, and tube formation, which were reversed by HY-15244 treatment. HY-15244 also inhibited the mRNA and protein expression of TGF-β/PI3K pathway components, which were partially rescued by UDDM extract.

Conclusion: UDDM particles promote bone tissue regeneration and angiogenesis in a CSD mouse model. UDDM extract facilitates proliferation, migration, and tube formation of HUVECs by activating the TGF-β/PI3K signaling pathway. These findings suggest that UDDM particles and extracts hold promise for therapeutic application in bone defect repair and vascularization.

HUVEC; TGF-β/PI3K signaling pathway; Undemineralized dentin matrix; blood vessel formation; critical-sized skull defect.