Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats
Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats
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DOI：
10.1186/s13287-020-01642-6
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发表时间：
2020-03-20
影响因子：
7.5
通讯作者：
Masaki, Takao
中科院分区：
文献类型：
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作者：
Ishiuchi, Naoki;Nakashima, Ayumu;Masaki, Takao
研究背景间充质干细胞（mesenchymal stem cells，MSCs）可通过旁分泌促进损伤组织的再生，低氧预处理可增强MSCs的旁分泌能力。在这项研究中，我们研究了低氧预处理的MSC对缺血再灌注损伤（IRI）大鼠肾纤维化和炎症的治疗效果。方法将来自大鼠和人的MSC在1%O-2条件下孵育（1%O-2 MSC）24 h。IRI后经腹主动脉注入1%O-2 MSCs或常氧条件下培养的MSCs（21%O-2 MSCs）。在注射后7或21天，处死大鼠并分析其肾脏。在体外实验中，我们研究了是否1%O-2间充质干细胞增强的能力，以产生抗纤维化的体液因子，使用转化生长因子（TGF）-β 1刺激的HK-2细胞与条件培养基从MSCs.ResultsAdministration大鼠1%O-2间充质干细胞（1%O-2 rMSCs）衰减肾纤维化和炎症比大鼠21%O-2间充质干细胞更显着。值得注意的是，人1%O-2 MSC（1%O-2 hMSC）也以与1%O-2 rMSC相同的程度减轻肾纤维化。流式细胞术显示1%O-2 hMSCs对人白细胞抗原表达无明显影响。进一步的体外实验显示，与21%O-2 MSC相比，来自1%O-2 MSC的条件培养基进一步抑制TGF-β 1诱导的HK-2细胞的纤维化变化。低氧预处理促进血管内皮生长因子（VEGF）和肝细胞生长因子（HGF）的分泌。有趣的是，在1%O-2 MSC中VEGF敲低减弱了HGF分泌和对TGF-β 1诱导的HK-2细胞纤维化变化的抑制。此外，VEGF敲低1%O-2 hMSCs减少IRI ratus.ConclusionsOur结果表明，缺氧预处理的骨髓间充质干细胞是有用的同种异体移植细胞治疗，以防止肾纤维化和炎症的抗纤维化作用。
BackgroundMesenchymal stem cells (MSCs) have been reported to promote the regeneration of injured tissue via their paracrine abilities, which are enhanced by hypoxic preconditioning. In this study, we examined the therapeutic efficacy of hypoxia-preconditioned MSCs on renal fibrosis and inflammation in rats with ischemia-reperfusion injury (IRI).MethodsMSCs derived from rats and humans were incubated in 1% O-2 conditions (1%O-2 MSCs) for 24h. After IRI, 1%O-2 MSCs or MSCs cultured under normoxic conditions (21%O-2 MSCs) were injected through the abdominal aorta. At 7 or 21days post-injection, the rats were sacrificed and their kidneys were analyzed. In in vitro experiments, we examined whether 1%O-2 MSCs enhanced the ability to produce anti-fibrotic humoral factors using transforming growth factor (TGF)-beta 1-stimulated HK-2 cells incubated with conditioned medium from MSCs.ResultsAdministration of rat 1%O-2 MSCs (1%O-2 rMSCs) attenuated renal fibrosis and inflammation more significantly than rat 21%O-2 MSCs. Notably, human 1%O-2 MSCs (1%O-2 hMSCs) also attenuated renal fibrosis to the same extent as 1%O-2 rMSCs. Flow cytometry showed that 1%O-2 hMSCs did not change human leukocyte antigen expression. Further in vitro experiments revealed that conditioned medium from 1%O-2 MSCs further suppressed TGF-beta 1-induced fibrotic changes in HK-2 cells compared with 21%O-2 MSCs. Hypoxic preconditioning enhanced vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) secretion. Interestingly, VEGF knockdown in 1%O-2 MSCs attenuated HGF secretion and the inhibition of TGF-beta 1-induced fibrotic changes in HK-2 cells. In addition, VEGF knockdown in 1%O-2 hMSCs reduced the anti-fibrotic effect in IRI rats.ConclusionsOur results indicate that hypoxia-preconditioned MSCs are useful as an allogeneic transplantation cell therapy to prevent renal fibrosis and inflammation.