Faculty of Dentistry, National University of Singapore, Singapore.
Institute of Medical Biology, Agency for Science, Technology and Research, Singapore.
Acta Biomater. 2019 Apr 15;89:252-264. doi: 10.1016/j.actbio.2019.03.021. Epub 2019 Mar 13.
Mesenchymal stem cells (MSCs) are potential therapeutics for the treatment of periodontal defects. It is increasingly accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly exosomes. Here, we investigated the therapeutic effects of human MSC exosome-loaded collagen sponge for regeneration of surgically created periodontal intrabony defects in an immunocompetent rat model. We observed that relative to control rats, exosome-treated rats repaired the defects more efficiently with regeneration of periodontal tissues including newly-formed bone and periodontal ligament (PDL). We also observed that concomitant with this, there was increased cellular infiltration and proliferation. We therefore postulated that MSC exosomes enhanced regeneration through increased cellular mobilisation and proliferation. Using PDL cell cultures, we demonstrated that MSC exosomes could increase PDL cell migration and proliferation through CD73-mediated adenosine receptor activation of pro-survival AKT and ERK signalling. Inhibition of AKT or ERK phosphorylation suppressed PDL cell migration and proliferation. Our findings demonstrated for the first time that MSC exosomes enhance periodontal regeneration possibly by increasing PDL migration and proliferation. This study suggests that MSC exosome is a viable ready-to-use and cell-free MSC therapeutic for the treatment of periodontal defects. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cell (MSC) therapies have demonstrated regenerative potential for the treatment of periodontal defects. However, translation of cellular therapies is hampered by challenges in maintaining optimal cell vitality and viability from manufacturing and storage to final delivery to patients. Although the use of MSCs for tissue repair was first predicated on their differentiation potential, the therapeutic efficacy of MSCs has increasingly been attributed to its paracrine secretion, particularly exosomes or small extracellular vesicles. In this study, MSC exosome-loaded collagen sponge enhanced periodontal regeneration in an immunocompetent rat periodontal defect model without any obvious adverse effects. These findings provide the basis for future development of MSC exosomes as a cell-free strategy for periodontal regeneration.
间充质干细胞 (MSCs) 是治疗牙周缺损的潜在治疗方法。越来越多的人认为，MSCs 通过分泌营养因子，特别是外泌体来介导组织修复。在这里，我们研究了负载人 MSC 外泌体的胶原海绵在免疫功能正常的大鼠牙周骨内缺损再生模型中的治疗效果。我们观察到，与对照组大鼠相比，外泌体处理组大鼠更有效地修复了缺损，牙周组织包括新形成的骨和牙周韧带 (PDL) 得到了再生。我们还观察到，同时，细胞浸润和增殖增加。因此，我们推测 MSC 外泌体通过增加细胞动员和增殖来增强再生。通过 PDL 细胞培养，我们证明 MSC 外泌体可以通过 CD73 介导的腺苷受体激活促进生存的 AKT 和 ERK 信号转导来增加 PDL 细胞迁移和增殖。抑制 AKT 或 ERK 磷酸化可抑制 PDL 细胞迁移和增殖。我们的研究结果首次表明，MSC 外泌体通过增加 PDL 迁移和增殖来增强牙周再生。这项研究表明，MSC 外泌体是一种可行的即用型、无细胞 MSC 治疗方法，可用于治疗牙周缺损。
间充质干细胞 (MSC) 治疗法已被证明具有治疗牙周缺损的再生潜力。然而，细胞疗法的转化受到从制造和储存到最终递送给患者的过程中保持最佳细胞活力和生存能力的挑战的阻碍。尽管 MSCs 用于组织修复的最初依据是其分化潜力，但 MSCs 的治疗功效越来越归因于其旁分泌分泌，特别是外泌体或小细胞外囊泡。在这项研究中，负载 MSC 外泌体的胶原海绵增强了免疫功能正常的大鼠牙周缺损模型中的牙周再生，没有任何明显的不良反应。这些发现为 MSC 外泌体作为一种无细胞策略用于牙周再生的未来发展提供了基础。
