Layered Double Hydroxide Nanoparticles with Osteogenic Effects as miRNA Carriers to Synergistically Promote Osteogenesis of MSCs
Layered Double Hydroxide Nanoparticles with Osteogenic Effects as miRNA Carriers to Synergistically Promote Osteogenesis of MSCs
复制标题
具有成骨作用的层状双氢氧化物纳米粒子作为miRNA载体协同促进MSCs成骨
DOI：
10.1021/acsami.1c14382
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发表时间：
2021-10-07
影响因子：
9.5
通讯作者：
Wang，Shilong
中科院分区：
文献类型：
--
作者：
Yang，Li;He，Xiaolie;Wang，Shilong
间充质干细胞（MSC）为基础的细胞疗法在再生医学的临床应用中，低效率的分化和不良的植入阻碍。层状双氢氧化物（layered double hydroxide，LDH）纳米粒子是一种具有良好生物相容性和阴离子交换性能的片状材料，在组织修复领域作为药物和核苷酸的载体得到了广泛的应用。然而，很少有研究关注LDH本身的生物学效应。在这项研究中，我们证明了LDH在刺激骨髓来源的骨髓间充质干细胞（BMSCs）的成骨分化中的新功能。LDH处理后，成骨相关基因的表达、碱性磷酸酶（ALP）活性和钙沉积显著增加。用RNA测序进行的机制分析显示LDH通过靶向LGR 5/β-连环蛋白轴促进骨生成。LDH还在LPS触发的炎症条件下灭活IKK/NF-κB信号，表明LDH在增强骨再生和减轻炎症反应方面具有双重益处。此外，我们利用LDH作为骨诱导性miRNA let-7 d的转运载体，协同调节BMSCs向成骨细胞谱系的分化。LDH/let-7 d复合物比单独的LDH更好地诱导成骨。对于细胞移植，将BMSCs接种在LDH/let-7 d掺入的纤维蛋白支架中，这在裸鼠皮下异位成骨模型中证明了增强的骨诱导能力。总之，这项研究提供了一种新的策略，通过LDH介导的miRNA let-7 d的传递有效和协同改善成骨，从而阐明了LDH在再生医学中的未来应用。
Inefficient differentiation and poor engraftment hinder the clinical applications of mesenchymal stem cell (MSC)-based cell therapies in regenerative medicine. Layered double hydroxide (LDH) nanoparticles are sheet-like materials with desirable biocompatibility and anion-exchange properties and have been widely applied as drug and nucleotide carriers in the field of tissue repair. However, few studies have focused on the biological effects of LDH itself. In this study, we demonstrated the novel function of LDH in stimulating osteogenic differentiation of bone marrow-derived MSCs (BMSCs). The expression of osteogenic-related genes, alkaline phosphatase (ALP) activity, and calcium deposits were significantly increased after LDH treatment. Mechanistic analysis performed with RNA sequencing revealed that LDH promoted osteogenesis by targeting the LGR5/β-catenin axis. LDH also inactivated IKK/NF-κB signaling under LPS-triggered inflamed conditions, suggesting the dual benefits of LDH in enhancing bone regeneration and alleviating the inflammatory response. Furthermore, we utilized LDH as the transport vehicle of the osteoinductive miRNA let-7d to synergistically regulate BMSCs toward the osteoblastic lineage. The LDH/let-7d complex resulted in a better induction of osteogenesis than LDH alone. For cell transplantation, BMSCs were seeded in LDH/let-7d-incorporated fibrin scaffolds, which proved enhanced osteoinduction capability in the subcutaneous ectopic osteogenesis model in nude mice. Taken together, this study provides a novel strategy for effective and synergistic improvement of osteogenesis via LDH-mediated delivery of miRNA let-7d, thus shedding light on the future application of LDH in regenerative medicine.