The Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Australia.
J Tissue Eng Regen Med. 2019 Nov;13(11):1978-1991. doi: 10.1002/term.2947. Epub 2019 Aug 7.
Bone marrow-derived mesenchymal stem/stromal cells (BMSCs) can differentiate into bone-forming osteoblasts, playing a crucial role in bone regeneration. Exosomes are naturally cell-secreted nanovesicles and are lately regraded as an emerging mediator of cellular communication in physiological and pathological conditions. The present study aimed at investigating the complex cellular communications, especially those among the differentiating BMSCs, immune cells (e.g., macrophages), and newly recruited BMSCs via exosome-mediated pathways. Exosomes were first isolated from osteogenically differentiating BMSCs at various stages (Day 0, Day 3, Day 7, and Day 14, respectively). The cellular uptake of isolated exosomes was examined in macrophages and human BMSCs (hBMSCs). The exosomes collected at various osteogenic differentiation stages (0d-exo, 3d-exo, 7d-exo, and 14d-exo) had no effect on the viability of hBMSCs. The uptake of exosomes (0d-exo, 3d-exo, and 7d-exo) significantly decreased proinflammatory-gene expression and the level of an M1 phenotypic marker. Our results then revealed that 3d-exo, 7d-exo, and 14d-exo led to a remarkable increase in mesenchymal stem/stromal cell migration. In addition, 0d-exo significantly promoted the expression of early osteogenic markers, such as alkaline phosphatase and bone morphogenetic protein 2, indicating a pro-osteogenic role of hBMSC-derived exosomes. Collectively, these results suggest that exosomes derived from differentiating mesenchymal stem/stromal cells play a unique osteoimmunomodulatory role in the regulation of bone dynamics.
骨髓间充质干细胞（BMSCs）可分化为成骨细胞，在骨再生中发挥关键作用。外泌体是天然的细胞分泌的纳米囊泡，最近被认为是生理和病理条件下细胞通讯的新兴介质。本研究旨在研究复杂的细胞通讯，特别是分化中的 BMSCs、免疫细胞（如巨噬细胞）和新募集的 BMSCs 之间通过外泌体介导的途径的通讯。首先从不同成骨分化阶段（分别为第 0 天、第 3 天、第 7 天和第 14 天）的成骨分化 BMSCs 中分离出外泌体。在巨噬细胞和人骨髓间充质干细胞（hBMSCs）中检测分离出的外泌体的细胞摄取情况。在各种成骨分化阶段（0d-exo、3d-exo、7d-exo 和 14d-exo）收集的外泌体对 hBMSCs 的活力没有影响。外泌体（0d-exo、3d-exo 和 7d-exo）的摄取显著降低了促炎基因的表达和 M1 表型标志物的水平。然后，我们的研究结果表明，3d-exo、7d-exo 和 14d-exo 导致间充质干细胞/基质细胞迁移显著增加。此外，0d-exo 显著促进了早期成骨标志物碱性磷酸酶和骨形态发生蛋白 2 的表达，表明 hBMSC 来源的外泌体具有促成骨作用。总之，这些结果表明，分化的间充质干细胞来源的外泌体在调节骨动力学方面发挥独特的骨免疫调节作用。
