Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026
WNT4 reprograms dental pulp stem cells to resist PANoptosis and rebuild neurogenic potential for facial nerve injury repair.
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Xu Wanqiu, Xi Hualei, Lin Song, Yao Lihong, Sun Jian, Xue Bing, Piao Guiyan, Liu Ying, Sun Wenjing, Wang Xiumei
Аннотация
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 × 106 cells) 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.
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 × 106 cells) 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.