Mouse Umbilical Cord Mesenchymal Stem Cell Paracrine Alleviates Renal Fibrosis in Diabetic Nephropathy by Reducing Myofibroblast Transdifferentiation and Cell Proliferation and Upregulating MMPs in Mesangial Cells
Mouse Umbilical Cord Mesenchymal Stem Cell Paracrine Alleviates Renal Fibrosis in Diabetic Nephropathy by Reducing Myofibroblast Transdifferentiation and Cell Proliferation and Upregulating MMPs in Mesangial Cells
复制标题
小鼠脐带间充质干细胞旁分泌通过减少肌成纤维细胞转分化和细胞增殖以及上调系膜细胞中的 MMP 来减轻糖尿病肾病的肾纤维化
DOI：
10.1155/2020/3847171
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发表时间：
2020-05-05
影响因子：
4.3
通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Li, Hongde;Rong, Pengfei;Wang, Wei
脐带间充质干细胞（UC-MSCs）移植是目前公认的治疗糖尿病肾病（DN）的新策略。然而，UC-MSCs改善DN肾纤维化的机制尚不清楚。在此，我们首先研究了小鼠UC-MSC输注对链脲佐菌素（STZ-）诱导的糖尿病小鼠肾脏结构和功能损害的治疗作用。我们发现重复注射mUC-MSCs可减轻DN小鼠模型的蛋白尿、肾小球损伤和纤维化。接下来，将系膜细胞暴露于5.6 mM葡萄糖、30 mM葡萄糖或mUC-MSC条件培养基，然后我们进行蛋白质印迹、免疫荧光、伤口愈合测定和细胞增殖测定以测量细胞外基质（ECM）蛋白和基质金属蛋白酶（MMP）、肌成纤维细胞转分化（MFT）和细胞增殖。我们证明mUC-MSC旁分泌通过抑制TGF-β1触发的MFT和PI 3 K/Akt和MAPK信号通路介导的细胞增殖以及升高MMP 2和MMP 9水平来减少纤连蛋白和胶原I的沉积。重要的是，我们提供的证据表明，mUC-MSC旁分泌在DN中的抗纤维化作用可能是由MSC脱落的外泌体决定的。这些结果揭示了UC-MSCs治疗DN肾纤维化的机制，为将来基于UC-MSCs的DN无细胞治疗提供了依据。
Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) is currently considered a novel therapeutic strategy for diabetic nephropathy (DN). However, the mechanisms by which UC-MSCs ameliorate renal fibrosis in DN are not well understood. Herein, we firstly investigated the therapeutic effects of mouse UC-MSC infusion on kidney structural and functional impairment in streptozotocin- (STZ-) induced diabetic mice. We found that the repeated injection with mUC-MSCs alleviates albuminuria, glomerulus injury, and fibrosis in DN mouse models. Next, mesangial cells were exposed to 5.6 mM glucose, 30 mM glucose, or mUC-MSC-conditioned medium, and then we performed western blotting, immunofluorescence, wound healing assay, and cell proliferation assay to measure extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), myofibroblast transdifferentiation (MFT), and cell proliferation. We demonstrated that mUC-MSC paracrine decreased the deposition of fibronectin and collagen I by inhibiting TGF-β1-triggered MFT and cell proliferation mediated by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. Importantly, we provided evidence that the antifibrosis role of mUC-MSC paracrine in DN might be determined by exosomes shed by MSCs. Together, these findings reveal the mechanisms underlying the therapeutic effects of UC-MSCs on renal fibrosis in DN and provide the evidence for DN cell-free therapy based on UC-MSCs in the future.