The Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Avenue, Kelvin Grove, Brisbane, Queensland 4059, Australia; The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, 60 Musk Avenue, Kelvin Grove, Brisbane, Queensland 4059, Australia.
The Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Avenue, Kelvin Grove, Brisbane, Queensland 4059, Australia; The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, 60 Musk Avenue, Kelvin Grove, Brisbane, Queensland 4059, Australia; Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 51050, China.
Acta Biomater. 2019 Mar 1;86:480-492. doi: 10.1016/j.actbio.2019.01.006. Epub 2019 Jan 7.
Exosomes are extracellular nanovesicles that play an important role in cellular communication. The modulatory effects of bone morphogenetic protein 2 (BMP2) on macrophages have encouraged the functionalization of scaffolds through the integration of the exosomes from the BMP2-stimulated macrophages to avoid ectopic bone formation and reduce adverse effects. To determine the functionality of exosomal nanocarriers from macrophages after BMP2 stimulation, we isolated the exosomes from Dulbecco's modified Eagle's medium (DMEM)- or BMP2-stimulated macrophages and evaluated their effects on osteogenesis. Morphological characterization of the exosomes derived from DMEM- or BMP2-treated macrophages revealed no significant differences, and the bone marrow-derived mesenchymal stromal cells showed similar cellular uptake patterns for both exosomes. In vitro study using BMP2/macrophage-derived exosomes indicated their beneficial effects on osteogenic differentiation. To improve the bio-functionality for titanium implants, BMP2/macrophage-derived exosomes were used to modify titanium nanotube implants to favor osteogenesis. The incorporation of BMP2/macrophage-derived exosomes dramatically increased the expression of early osteoblastic differentiation markers, alkaline phosphatase (ALP) and BMP2, indicative of the pro-osteogenic role of the titanium nanotubes incorporated with BMP2/macrophage-derived exosomes. The titanium nanotubes functionalized with BMP2/macrophage-derived exosomes activated autophagy during osteogenic differentiation. In conclusion, the exosome-integrated titanium nanotube may serve as an emerging functional material for bone regeneration. STATEMENT OF SIGNIFICANCE: The clinical application of bone morphogenetic protein 2 (BMP2) is often limited by its side effects. Exosomes are naturally secreted nanosized vesicles derived from cells and play an important role in intercellular communication. The contributions of this study include (1) the demonstration of the potential regulatory role of BMP2/macrophage-derived exosomes on the osteogenic differentiation of mesenchymal stromal cells (MSCs); (2) fabrication of titanium nanotubes incorporated with exosomes; (3) new insights into the application of titanium nanotube-based materials for the safe use of BMP2.
外泌体是一种细胞外的纳米囊泡，在细胞通讯中发挥着重要作用。骨形态发生蛋白 2（BMP2）对巨噬细胞的调节作用鼓励通过整合 BMP2 刺激的巨噬细胞来源的外泌体来功能化支架，以避免异位骨形成和减少不良反应。为了确定 BMP2 刺激后巨噬细胞来源的外泌体纳米载体的功能，我们从 DMEM 或 BMP2 刺激的巨噬细胞中分离出外泌体，并评估它们对成骨的影响。来自 DMEM 或 BMP2 处理的巨噬细胞的外泌体的形态特征显示没有显著差异，骨髓间充质基质细胞对两种外泌体的摄取模式相似。使用 BMP2/巨噬细胞来源的外泌体的体外研究表明它们对成骨分化有有益的影响。为了提高钛植入物的生物功能，使用 BMP2/巨噬细胞来源的外泌体来修饰钛纳米管植入物以促进成骨。BMP2/巨噬细胞来源的外泌体的掺入极大地增加了早期成骨分化标志物碱性磷酸酶（ALP）和 BMP2 的表达，表明掺入 BMP2/巨噬细胞来源的外泌体的钛纳米管具有促成骨作用。功能化有 BMP2/巨噬细胞来源的外泌体的钛纳米管在成骨分化过程中激活自噬。总之，整合了外泌体的钛纳米管可用作骨再生的新兴功能材料。 意义声明：骨形态发生蛋白 2（BMP2）的临床应用常受到其副作用的限制。外泌体是源自细胞的天然分泌的纳米尺寸囊泡，在细胞间通讯中发挥着重要作用。本研究的贡献包括（1）证明 BMP2/巨噬细胞来源的外泌体对间充质基质细胞（MSCs）成骨分化的潜在调节作用；（2）制备了外泌体包被的钛纳米管；（3）为基于钛纳米管的材料在安全使用 BMP2 方面的应用提供了新的见解。
