Deng Pingmeng, Yang Bin, Huang Chuling, Li Yuejia, Mei Ziyi, Li Yong, Li Jie
College of Stomatology, Chongqing Medical University, Chongqing, PR China.
Chongqing Key Laboratory of Oral Diseases, Chongqing, PR China.
J Tissue Eng. 2025 Jul 28;16:20417314251357752. doi: 10.1177/20417314251357752. eCollection 2025 Jan-Dec.
Mesenchymal stem cell-mediated bone tissue engineering strategies, including human dental pulp stem cells (hDPSCs), represent an effective therapeutic approach for bone defect repair, particularly in maxillofacial bone defects. Growth differentiation factor 15 (GDF15), a multifunctional cytokine, plays a critical role in bone tissue formation and remodeling. This study aims to investigate the effects of GDF15 on the osteogenic differentiation of hDPSCs and elucidate the underlying molecular mechanisms. Our findings demonstrate that GDF15 expression and secretion are upregulated during the osteogenic differentiation of hDPSCs. Both overexpression and recombinant human GDF15 (rhGDF15) treatment significantly enhanced the osteogenic differentiation of hDPSCs, whereas knockdown produced the opposite effect. experiments demonstrated that hDPSCs treated with rhGDF15 significantly enhanced new bone formation within implants in both nude mouse subcutaneous transplantation and rat calvarial defect models. Proteomic analysis identified significant enrichment of the TGF-β/SMAD signaling pathway. Molecular docking analysis and co-immunoprecipitation demonstrated the direct binding interaction between GDF15 and TGF-βR2. Both Western blotting and immunofluorescence assays confirmed pathway activation. Critically, pharmacological inhibition of this pathway partially reversed the rhGDF15-induced enhancement of osteogenic differentiation in hDPSCs. Collectively, our findings demonstrate that GDF15 promotes osteogenic differentiation of hDPSCs through activation of the TGF-β/SMAD signaling pathway, thereby proposing a novel therapeutic strategy for bone repair and regenerative treatment.
间充质干细胞介导的骨组织工程策略，包括人牙髓干细胞（hDPSC），是骨缺损修复的一种有效治疗方法，尤其适用于颌面骨缺损。生长分化因子15（GDF15）是一种多功能细胞因子，在骨组织形成和重塑中起关键作用。本研究旨在探讨GDF15对hDPSC成骨分化的影响，并阐明其潜在的分子机制。我们的研究结果表明，在hDPSC成骨分化过程中，GDF15的表达和分泌上调。过表达和重组人GDF15（rhGDF15）处理均显著增强了hDPSC的成骨分化，而敲低则产生相反的效果。实验表明，在裸鼠皮下移植和大鼠颅骨缺损模型中用rhGDF15处理的hDPSC显著增强了植入物内的新骨形成。蛋白质组学分析确定了TGF-β/SMAD信号通路的显著富集。分子对接分析和免疫共沉淀证明了GDF15与TGF-βR2之间的直接结合相互作用。蛋白质印迹和免疫荧光测定均证实了该信号通路被激活。至关重要的是，该信号通路的药理学抑制部分逆转了rhGDF15诱导的hDPSC成骨分化增强。总的来说，我们的研究结果表明，GDF15通过激活TGF-β/SMAD信号通路促进hDPSC成骨分化，从而为骨修复和再生治疗提出了一种新的治疗策略。
