WNT4 reprograms dental pulp stem cells to resist PANoptosis and rebuild neurogenic potential for facial nerve injury repair
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Objective and design This study investigated the protective role and molecular mechanism of WNT4 in preserving the viability and neurogenic potential of dental pulp stem cells (DPSCs) within an inflammatory microenvironment following facial nerve injury (FNI). Material or subjects Human DPSCs (hDPSCs; authenticated by surface marker profiling and multi-lineage differentiation) and a rat model of facial nerve transection (n = 15 per group) were utilized. Treatment In vitro, hDPSCs were treated with TNF-α(10 ng/mL) to model inflammation. In vivo, WNT4-overexpressing or control DPSCs (1 × 10cells) were injected into the tail vein immediately after nerve transection. Methods PANoptosis and neurogenic differentiation were assessed by Western blot, flow cytometry, and immunofluorescence staining. Transcriptional regulation was analyzed by dual-luciferase reporter assay and ChIP-qPCR. Protein interaction was examined by LC–MS/MS and docking. In vivo recovery was monitored by functional assessments and histology. Results WNT4 overexpression significantly attenuated TNF-α-induced PANoptosis in hDPSCs and restored their neurogenic potential. Mechanistically, KLF7 transcriptionally activated WNT4. WNT4 interacted with NOTCH1, activating Wnt/β-catenin signaling and upregulating c-Jun, CYCD1, and VEGFA. In vivo, engineered hDPSCs reduced local inflammation and accelerated functional recovery and histological repair. Conclusions WNT4 protects DPSCs against inflammatory PANoptosis and enhan
Abstract
Objective and design This study investigated the protective role and molecular mechanism of WNT4 in preserving the viability and neurogenic potential of dental pulp stem cells (DPSCs) within an inflammatory microenvironment following facial nerve injury (FNI). Material or subjects Human DPSCs (hDPSCs; authenticated by surface marker profiling and multi-lineage differentiation) and a rat model of facial nerve transection (n = 15 per group) were utilized. Treatment In vitro, hDPSCs were treated with TNF-α(10 ng/mL) to model inflammation. In vivo, WNT4-overexpressing or control DPSCs (1 × 10cells) were injected into the tail vein immediately after nerve transection. Methods PANoptosis and neurogenic differentiation were assessed by Western blot, flow cytometry, and immunofluorescence staining. Transcriptional regulation was analyzed by dual-luciferase reporter assay and ChIP-qPCR. Protein interaction was examined by LC–MS/MS and docking. In vivo recovery was monitored by functional assessments and histology. Results WNT4 overexpression significantly attenuated TNF-α-induced PANoptosis in hDPSCs and restored their neurogenic potential. Mechanistically, KLF7 transcriptionally activated WNT4. WNT4 interacted with NOTCH1, activating Wnt/β-catenin signaling and upregulating c-Jun, CYCD1, and VEGFA. In vivo, engineered hDPSCs reduced local inflammation and accelerated functional recovery and histological repair. Conclusions WNT4 protects DPSCs against inflammatory PANoptosis and enhances neuroreparative potential, providing a basis for optimizing stem cell therapy in FNI. Supplementary Information The online version contains supplementary material available at 10.1007/s00011-026-02296-5. Abs1