The transplantation of rapamycin-treated senescent human mesenchymal stem cells with enhanced proangiogenic activity promotes neovascularization and ischemic limb salvage in mice
The transplantation of rapamycin-treated senescent human mesenchymal stem cells with enhanced proangiogenic activity promotes neovascularization and ischemic limb salvage in mice
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DOI：
10.1038/s41401-022-00896-5
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发表时间：
2022-04
影响因子：
8.2
通讯作者：
Yu-lin Cao;Wen-lan Chen;Qian Lei;Fei Gao;Wen-xiang Ren;Li Chen;Hongxiang Wang;Ting Chen
中科院分区：
文献类型：
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作者：
Yu-lin Cao;Wen-lan Chen;Qian Lei;Fei Gao;Wen-xiang Ren;Li Chen;Hongxiang Wang;Ting Chen
很少有治疗方法可以逆转衰老间充质基质/干细胞（MSCs）的促血管生成活性。在这项研究中，我们研究了雷帕霉素对衰老人脐带间充质干细胞（UCMSCs）促血管生成能力的影响。在体外培养的UCMSCs中建立了体外复制衰老细胞模型。我们发现晚期传代（P25或更晚）的UCMSCs （LP-UCMSCs）表现出促血管生成能力受损。用雷帕霉素（900 nM）处理P25 UCMSCs可逆转衰老表型，并显著增强衰老UCMSCs的促血管生成活性。在裸鼠后肢缺血模型中，肌肉注射雷帕霉素处理的P25 UCMSCs可显著促进缺血肢体新生血管的形成和缺血肢体的保留。我们进一步分析了雷帕霉素诱导的MSCs中血管生成相关基因的表达变化，发现几种与血管生成相关的基因，如vegfr2和ctgf /CCN2，在引物细胞中比在未引物的MSCs中表达更高。综上所述，我们的数据表明雷帕霉素是一种潜在的药物，可以恢复衰老间充质干细胞的促血管生成活性，这在治疗缺血性疾病和组织工程中具有重要意义。
Few therapies can reverse the proangiogenic activity of senescent mesenchymal stromal/stem cells (MSCs). In this study, we investigated the effects of rapamycin on the proangiogenic ability of senescent human umbilical cord MSCs (UCMSCs). An in vitro replicative senescent cell model was established in cultured UCMSCs. We found that late passage (P25 or later) UCMSCs (LP-UCMSCs) exhibited impaired proangiogenic abilities. Treatment of P25 UCMSCs with rapamycin (900 nM) reversed the senescent phenotype and notably enhanced the proangiogenic activity of senescent UCMSCs. In a nude mouse model of hindlimb ischemia, intramuscular injection of rapamycin-treated P25 UCMSCs into the ischemic limb significantly promoted neovascularization and ischemic limb salvage. We further analyzed the changes in the expression of angiogenesis-associated genes in rapamycin-primed MSCs and found higher expression of several genes related to angiogenesis, such asVEGFR2andCTGF/CCN2, in primed cells than in unprimed MSCs. Taken together, our data demonstrate that rapamycin is a potential drug to restore the proangiogenic activity of senescent MSCs, which is of importance in treating ischemic diseases and tissue engineering.