Quaking Is a Key Regulator of Endothelial Cell Differentiation, Neovascularization, and Angiogenesis.
Quaking Is a Key Regulator of Endothelial Cell Differentiation, Neovascularization, and Angiogenesis.
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DOI：
10.1002/stem.2594
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Margariti A
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文献类型：
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作者：
Cochrane A;Kelaini S;Tsifaki M;Bojdo J;Vilà-González M;Drehmer D;Caines R;Magee C;Eleftheriadou M;Hu Y;Grieve D;Stitt AW;Zeng L;Xu Q;Margariti A
从诱导多能干细胞（iPSC）衍生内皮细胞（EC）的能力对于心血管疾病具有巨大的治疗潜力。这项研究阐明了RNA结合蛋白Quaking同种型5（QKI-5）在小鼠和人iPSC（hiPSC）EC分化过程中的确切作用，并分析了RNA结合蛋白如何提高重要血管疾病细胞治疗的分化效率。iPSC代表了当今再生医学的一种有吸引力的细胞方法，因为它们可用于产生患者特异性治疗细胞，用于自体细胞治疗。在这项研究中，使用iPSC向EC分化的模型，发现QKI-5是EC分化过程中STAT 3稳定和血管内皮生长因子受体2（VEGFR 2）活化的重要调节因子。QKI-5在EC分化过程中被诱导，导致STAT 3表达的稳定和VEGFR 2转录激活的调节，以及通过直接结合到STAT 3的3′ UTR的VEGF分泌。重要的是，过表达QKI-5的小鼠iPS-EC显著改善了实验性后肢缺血中的血管生成和新血管形成以及血流恢复。值得注意的是，过表达QKI-5的hiPSC在SCID小鼠中皮下注射后仅7天就在体内基质胶塞测定中诱导血管生成。这些结果突出了QKI-5在新生血管形成、血流恢复和血管生成方面的明确功能获益。因此，他们提供了越来越多的共识，阐明EC分化的分子机制将最终推进干细胞再生治疗，并最终使心血管疾病的治疗成为现实。RNA结合蛋白QKI-5在从iPSC分化EC期间被诱导。在EC分化过程中，与EC标志物CD 144平行诱导RNA结合蛋白QKI-5。免疫荧光染色显示QKI-5定位于细胞核中，并与分化的EC中的CD 144平行染色（比例尺= 50 µm）。干细胞2017干细胞2017;35：952-966
The capability to derive endothelial cell (ECs) from induced pluripotent stem cells (iPSCs) holds huge therapeutic potential for cardiovascular disease. This study elucidates the precise role of the RNA‐binding protein Quaking isoform 5 (QKI‐5) during EC differentiation from both mouse and human iPSCs (hiPSCs) and dissects how RNA‐binding proteins can improve differentiation efficiency toward cell therapy for important vascular diseases. iPSCs represent an attractive cellular approach for regenerative medicine today as they can be used to generate patient‐specific therapeutic cells toward autologous cell therapy. In this study, using the model of iPSCs differentiation toward ECs, the QKI‐5 was found to be an important regulator of STAT3 stabilization and vascular endothelial growth factor receptor 2 (VEGFR2) activation during the EC differentiation process. QKI‐5 was induced during EC differentiation, resulting in stabilization of STAT3 expression and modulation of VEGFR2 transcriptional activation as well as VEGF secretion through direct binding to the 3′ UTR of STAT3. Importantly, mouse iPS‐ECs overexpressing QKI‐5 significantly improved angiogenesis and neovascularization and blood flow recovery in experimental hind limb ischemia. Notably, hiPSCs overexpressing QKI‐5, induced angiogenesis on Matrigel plug assays in vivo only 7 days after subcutaneous injection in SCID mice. These results highlight a clear functional benefit of QKI‐5 in neovascularization, blood flow recovery, and angiogenesis. Thus, they provide support to the growing consensus that elucidation of the molecular mechanisms underlying EC differentiation will ultimately advance stem cell regenerative therapy and eventually make the treatment of cardiovascular disease a reality. The RNA binding protein QKI‐5 is induced during EC differentiation from iPSCs. RNA binding protein QKI‐5 was induced during EC differentiation in parallel with the EC marker CD144. Immunofluorescence staining showing that QKI‐5 is localized in the nucleus and stained in parallel with CD144 in differentiated ECs (scale bar = 50 µm). stem cells 2017 Stem Cells 2017;35:952–966