Pervaiz Iqra, Mehta Yash, Al-Ahmad Abraham Jacob
Department of Pharmaceutical Sciences and Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
J Cell Physiol. 2025 Jan;240(1):e31523. doi: 10.1002/jcp.31523.
Glucose is a major source of energy for the brain. At the blood-brain barrier (BBB), glucose uptake is facilitated by glucose transporter 1 (GLUT1). GLUT1 Deficiency Syndrome (GLUT1DS), a haploinsufficiency affecting SLC2A1, reduces glucose brain uptake. A lot of effort has been made to characterize GLUT1DS at the BBB, but the impact on astrocytes remains unclear. In this study, we investigated the impact of GLUT1DS on astrocyte differentiation and function in vitro, using human induced pluripotent stem cells GLUT1DS (GLUT1DS-iPSCs) differentiated into astrocyte-like cells (iAstros). GLUT1 expression is decreased during the differentiation of iPSCs into astrocytes, with neural progenitor cells showing the lowest expression. The presence of a truncated GLUT1 did not compromise the differentiation of iPSCs into iAstros, as these cells could express several key markers representative of the astrocyte lineage. GLUT1DS-iAstros failed to express full-length GLUT1 at protein levels while showing no signs of impaired GLUT4 expression. However, GLUT1DS-iAstros showed decreased glucose uptake and lactate production compared to control-iAstros, reduced glycolysis, and mitochondrial activity as well as ATP deficit. In addition to reduced energy production, astrocytes displayed a reduced extracellular glutamate release. As previously observed, one iAstros clone (C7) showed the most severe phenotype from all groups. Our study provides an insightful view of the contribution of GLUT1 in astrocytes' energetic metabolism and raises the possible contribution of these cells in the astrocyte-neuron metabolic coupling. Our future direction is to understand better how GLUT1DS impacts astrocytes and neurons within their metabolic coupling.
葡萄糖是大脑的主要能量来源。在血脑屏障（BBB）处，葡萄糖转运蛋白1（GLUT1）促进葡萄糖的摄取。GLUT1缺乏综合征（GLUT1DS）是一种影响SLC2A1的单倍体不足症，会降低大脑对葡萄糖的摄取。人们已经付出了很多努力来表征BBB处的GLUT1DS，但对星形胶质细胞的影响仍不清楚。在本研究中，我们使用分化为星形胶质样细胞（iAstros）的人诱导多能干细胞GLUT1DS（GLUT1DS-iPSCs），研究了GLUT1DS对体外星形胶质细胞分化和功能的影响。在iPSCs分化为星形胶质细胞的过程中，GLUT1的表达会降低，神经祖细胞的表达最低。截短的GLUT1的存在并不影响iPSCs向iAstros的分化，因为这些细胞可以表达几种代表星形胶质细胞谱系的关键标志物。GLUT1DS-iAstros在蛋白质水平上未能表达全长GLUT1，同时未显示出GLUT4表达受损的迹象。然而，与对照iAstros相比，GLUT1DS-iAstros的葡萄糖摄取和乳酸生成减少，糖酵解、线粒体活性降低以及ATP缺乏。除了能量产生减少外，星形胶质细胞的细胞外谷氨酸释放也减少。如先前观察到的，一个iAstros克隆（C7）在所有组中表现出最严重的表型。我们的研究深入了解了GLUT1在星形胶质细胞能量代谢中的作用，并提出了这些细胞在星形胶质细胞-神经元代谢偶联中的可能作用。我们未来的方向是更好地了解GLUT1DS如何在其代谢偶联中影响星形胶质细胞和神经元。
