Klotho gene-modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β-catenin pathway in kidneys after acute injury
Klotho gene-modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β-catenin pathway in kidneys after acute injury
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Klotho 基因修饰的 BMSC 通过抑制急性损伤后肾脏中的 Wnt/β-catenin 通路，表现出增强的抗纤维化作用
DOI：
10.1002/cbin.11068
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发表时间：
2018
影响因子：
3.9
通讯作者：
Chang Chun Cao
中科院分区：
文献类型：
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作者：
Feng Zhang;Xin Wan;Yi Zhi Cao;Dong Sun;Chang Chun Cao
Klotho是主要在肾小管上皮细胞中表达的蛋白质。研究表明Klotho是一种抗衰老蛋白，可减少急性肾损伤（阿基）后的肾纤维化并抑制干细胞衰老。骨髓间充质干细胞（BMSCs）具有稳定的增殖能力和多向分化能力，已被用于治疗组织损伤。因此，我们假设Klotho在BMSCs中表达可以增加BMSCs的肾脏保护作用。为了验证这一假设，我们从C57 BL/6小鼠中分离BMSC，用Klotho-GFP-腺病毒转染它们，并研究BMSC增殖的变化。然后，我们将Klotho‐GFP‐ BMSC移植到患有阿基的小鼠中，并与假治疗小鼠和GFP‐BMSC移植小鼠相比研究治疗效果。骨髓间充质干细胞移植可减轻缺血再灌注损伤（IRI）后的肾纤维化，过表达Klotho基因可显著增强骨髓间充质干细胞的抗纤维化作用。机制研究表明Klotho增加了BMSCs中多能性基因的表达。Klotho‐GFP‐ BMSC产生的Klotho抑制肾小管上皮细胞（TEC）中的Wnt/β-catenin通路。Klotho-GFP-BMSCs显示出比GFP-BMSCs更强的增殖能力和更强的免疫调节能力。我们的研究结果表明，Klotho基因修饰的BMSCs可能是阿基后细胞治疗的更好选择。
Klotho is a protein primarily expressed in renal tubular epithelial cells. Studies have suggested that Klotho is an antiaging protein that reduces renal fibrosis after acute kidney injury (AKI) and inhibits stem cell senescence. Bone marrow mesenchymal stem cells (BMSCs) have consistent proliferation ability and multidirectional differentiation ability and have been used to treat tissue injury. Thus, we hypothesized that Klotho expressed in BMSCs could increase the renal protective effects of BMSCs. To verify the hypothesis, we isolated BMSCs from C57BL/6 mice, transfected them with Klotho‐GFP‐adenovirus and investigated the change in BMSC proliferation. We then transplanted Klotho‐GFP‐BMSCs into mice with AKI and investigated the therapeutic effect compared with that of sham‐treated mice and GFP‐BMSC‐transplanted mice. Kidney fibrosis after ischemia/reperfusion injury (IRI) was relieved by BMSC transplantation, and the antifibrotic effect of BMSCs was significantly enhanced by overexpressing the Klotho gene. Mechanistic studies showed that Klotho increased pluripotency gene expression in BMSCs. Klotho produced by Klotho‐GFP‐BMSCs inhibited the Wnt/β‐catenin pathway in renal tubular epithelial cells (TECs). Klotho‐GFP‐BMSCs showed increased proliferative ability and more potent immuno‐regulation ability than did GFP‐BMSCs. Our findings suggested that Klotho gene‐modified BMSCs may be a better choice for cell therapy after AKI.