GLUT4 expression and glucose transport in human induced pluripotent stem cell-derived cardiomyocytes
GLUT4 expression and glucose transport in human induced pluripotent stem cell-derived cardiomyocytes
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DOI：
10.1371/journal.pone.0217885
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发表时间：
2019-07-25
期刊：
影响因子：
3.7
通讯作者：
Gould, Gwyn W.
中科院分区：
文献类型：
--
作者：
Bowman, Peter R. T.;Smith, Godfrey L.;Gould, Gwyn W.
诱导多能干细胞来源的心肌细胞(IPSC-CM)具有改变再生心脏医学和心脏病模型的潜力。这在糖尿病心肌病的情况下尤其重要，糖尿病患者在没有血管疾病的情况下心脏舒张期收缩性能降低，这显著地导致了心血管疾病的高发病率。在这项研究中，评估了IPSC-CM作为一种新的心肌细胞模型的能力。糖尿病的表型以胰岛素抵抗为特征，因此特别关注代谢参数。尽管IPSC-CM表达关键的胰岛素信号中间体和相关的运输蛋白，但已被证实不表现出胰岛素刺激的葡萄糖摄取。IPSC-CM是自发收缩的，但收缩介导的摄取并不能掩盖任何胰岛素反应。在这些细胞中发现的基本限制是严重缺乏胰岛素敏感的葡萄糖转运体GLUT4的表达。使用比较免疫印迹分析和GLUT选择性抑制剂Bay-876来量化这些转运蛋白的表达，我们发现与原代心肌细胞和培养的脂肪细胞相比，IPSC-CM表达高水平的GLUT1和低水平的GLUT4。克服这一限制的干预措施未获成功。我们认为IPSC-CMS在心脏代谢紊乱研究中的应用可能受到其明显的胎儿样表型的限制。
Induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) have the potential to transform regenerative cardiac medicine and the modelling of cardiac disease. This is of particular importance in the context of diabetic cardiomyopathy where diabetic individuals exhibit reduced cardiac diastolic contractile performance in the absence of vascular disease, significantly contributing towards high cardiovascular morbidity. In this study, the capacity of iPSC-CM to act as a novel cellular model of cardiomyocytes was assessed. The diabetic phenotype is characterised by insulin resistance, therefore there was a specific focus upon metabolic parameters. Despite expressing crucial insulin signalling intermediates and relevant trafficking proteins, it was identified that iPSC-CM do not exhibit insulin-stimulated glucose uptake. iPSC-CM are spontaneously contractile however contraction mediated uptake was not found to mask any insulin response. The fundamental limitation identified in these cells was a critical lack of expression of the insulin sensitive glucose transporter GLUT4. Using comparative immunoblot analysis and the GLUT-selective inhibitor BAY-876 to quantify expression of these transporters, we show that iPSC-CM express high levels of GLUT1 and low levels of GLUT4 compared to primary cardiomyocytes and cultured adipocytes. Interventions to overcome this limitation were unsuccessful. We suggest that the utility of iPSC-CMs to study cardiac metabolic disorders may be limited by their apparent foetal-like phenotype.