Senescence-regulating agents remodel mesenchymal stem cell-schwann cell circuitry for diabetic bone regeneration.

An Lao, Yiting Sun, Weiqi Li, Yu Zhuang, Ziyang Liu, Chenci Xu, Xiangbing Wu, Linhu Ge, Kaili Lin, Jianyong Wu, Jing Mao, Jiaqiang Liu

Department of Stomatology, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Department of Oral and Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China. Electronic address: [email protected]. · pubmed

Paper

Abstract

Bone healing requires Schwann cells (SCs) paracrine factors for mesenchymal stem cell function. Diabetes mellitus (DM) patients are susceptible to developing SCs dysfunction and impairing bone healing. Rare research considered reconstructing mesenchymal stem cell-schwann cell circuitry in diabetic bone regeneration. Here we found that SCs in diabetic microenvironment appeared cellular senescence phenotype with excessive reactive oxygen species (ROS) and mitochondrial dysfunction. To target at senescent SCs, we co-entrapped small interfering RNA that targets P53 (Si-P53) and metformin (MET) in ZIF-8-based nanoparticles (MMZ@Si-P53). Mechanistically, MMZ@Si-P53 affected senescent SCs by promoting mitochondria recovery and serine biosynthesis. In addition, rejuvenation of SCs and recovery of mesenchymal stem cell-schwann cell circuitry inhibited bone marrow mesenchymal stem cells (BMSCs) senescence and improved BMSCs ossification. Subsequently MMZ@Si-P53 loaded into glucose-responsive hydrogel system (MMZ@Si-P53/HAMA-PBA-PVA) for triggering release of nanoparticles in hyperglycemia. MMZ@Si-P53/HAMA-PBA-PVA strongly promoted diabetic bone regeneration in diabetic rat model. Our findings demonstrated the effectiveness of MMZ@Si-P53/HAMA-PBA-PVA system in repairing diabetic bone defects.

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Research summary

The paper claims that the co-entrapped Si-P53 and metformin in nanoparticles can rejuvenate Schwann cells and improve mesenchymal stem cell function, leading to enhanced diabetic bone regeneration. This research addresses cellular senescence and its role in aging-related dysfunction, specifically in the context of diabetes, which is relevant to understanding and potentially mitigating age-related decline in tissue regeneration.

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