Bone marrow-derived humoral factors suppress oxidative phosphorylation, upregulate TSG-6, and improve therapeutic effects on liver injury of mesenchymal stem cells
Bone marrow-derived humoral factors suppress oxidative phosphorylation, upregulate TSG-6, and improve therapeutic effects on liver injury of mesenchymal stem cells
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DOI：
10.3164/jcbn.19-125
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发表时间：
2020-05-01
影响因子：
2.4
通讯作者：
Sakaida, Isao
中科院分区：
文献类型：
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作者：
Miyaji, Takashi;Takami, Taro;Sakaida, Isao
间充质干细胞具有用于再生医学的潜力，但需要提高患者使用的质量。为了保持培养的骨髓间充质干细胞的干性，我们关注骨髓微环境，生成全骨髓细胞条件培养基（BMC-CM），并评估其对骨髓间充质干细胞的影响。 BMC-CM 抑制培养的骨髓间充质干细胞的形态恶化和增殖衰退，抑制线粒体氧化磷酸化活性（干性指标），上调氧化磷酸化抑制剂，如缺氧诱导因子 1 α、Sirtuin 3、4 和 5。此外，BMC-CM 上调 TNF 刺激基因 6，改善细胞对碳肝损伤的治疗效果给予四氯化物的大鼠。由于消除 20-220 nm 颗粒会减弱 BMC-CM 的作用，因此我们进一步分析了全骨髓细胞产生的外泌体 microRNA。在 BMC-CM 制备过程中观察到上调的 49 个 microRNA 中，有几个被发现与抑制氧化磷酸化、上调 TNF 刺激基因 6 以及肝脏疾病的发病机制有关。因此，包括外泌体microRNA在内的骨髓源性体液因子可能有助于提高骨髓间充质干细胞用于肝脏再生治疗的治疗质量。
Mesenchymal stem cells, which have the potential to be used in regenerative medicine, require improvements in quality for patient use. To maintain stemness of cultured bone marrow-derived mesenchymal stem cells, we focused on the bone marrow microenvironment, generated a conditioned medium of whole bone marrow cells (BMC-CM), and assessed its effects on bone marrow-derived mesenchymal stem cells. BMC-CM suppressed morphological deterioration and proliferative decline in cultured bone marrow-derived mesenchymal stem cells, suppressed mitochondrial oxidative phosphorylation activity, a stemness indicator, and upregulated suppressors of oxidative phosphorylation such as hypoxia-inducible factor-1 alpha, Sirtuin 3, 4, and 5. Furthermore, BMC-CM upregulated TNF-stimulated gene 6 and ameliorated the therapeutic effects of cells on liver injury in carbon tetrachloride-administered rats. Since the elimination of 20-220-nm particles attenuated the effects of BMC-CM, we further analyzed exosomal microRNAs produced by whole bone marrow cells. Among the 49 microRNAs observed to be upregulated during the preparation of BMC-CM, several were identified that were associated with suppression of oxidative phosphorylation, upregulation of TNF-stimulated gene 6, and the pathogenesis of liver diseases. Thus, bone marrow-derived humoral factors including exosomal microRNAs may help to improve the therapeutic quality of bone marrow-derived mesenchymal stem cells for liver regenerative therapy.