A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes

IF 10.8 1区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE

International Journal of Oral Science Pub Date : 2024-12-01 DOI:10.1038/s41368-024-00328-6

Lingxiao Wang, Haoqing Yang, Chen Zhang, Yue Zhang, Yilin He, Yang Liu, Pan Ma, Jun Li, Zhipeng Fan

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Abstract

Blood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.

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血糖波动响应递送系统促进骨再生和smpd3重编程bmsc衍生外泌体的修复功能

血糖波动导致2型糖尿病（T2DM）患者骨缺损修复不良。如何安全有效地改善由血糖波动引起的骨再生障碍仍然是一个挑战。中性鞘磷脂酶2 （Smpd3）在T2DM患者颌骨源性骨髓间充质干细胞（BMSCs）中下调。在这里，我们研究了Smpd3对骨髓间充质干细胞成骨分化的影响，并利用过表达Smpd3的干细胞外泌体作为主要处理方法，基于苯硼酸基聚乙烯醇交联剂的葡萄糖反应性和明胶纳米颗粒的蛋白酶降解性。将过表达smpd3的干细胞衍生外泌体（Exos-Smpd3）和纳米银离子（Ns）联合负载构建水凝胶递送系统（Exos-Smpd3@Ns），可促进葡萄糖波动环境下骨髓间充质干细胞的成骨和分化、葡萄糖波动环境下骨髓间充质干细胞的异位成骨以及糖尿病犬的体外颌骨再生。机制上，Smpd3通过激活颌骨自噬，抑制血糖波动引起的巨噬细胞极化和氧化应激，促进颌骨源性骨髓间质干细胞成骨分化。这些结果揭示了Smpd3及Smpd3过表达外泌体递送系统在血糖波动下促进BMSC功能和骨再生中的作用和机制，为T2DM患者骨缺损的治疗提供了理论基础和候选方法。

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来源期刊

International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-

CiteScore

31.80

自引率

1.30%

发文量

审稿时长

>12 weeks

期刊介绍： The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.