Establishment and directed differentiation of induced pluripotent stem cells from glycogen storage disease type Ib patient
Establishment and directed differentiation of induced pluripotent stem cells from glycogen storage disease type Ib patient
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DOI：
10.1111/gtc.12101
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发表时间：
2013-12-01
期刊：
影响因子：
2.1
通讯作者：
Matsunaga, Tamihide
中科院分区：
文献类型：
--
作者：
Satoh, Daisuke;Maeda, Tohru;Matsunaga, Tamihide
糖原储存病Ib型（GSDIb）是由葡萄糖-6-磷酸转运体（G6PT）缺乏引起的，导致中性粒细胞功能障碍。然而，这些功能障碍的潜在原因及其与葡萄糖稳态的关系尚不清楚。诱导多能干细胞（iPSCs）在发育生物学、细胞治疗和人类疾病建模方面有着巨大的发展前景。在这里，我们研究了使用iPSCs作为GSDIb的模型。在这项研究中，一名2岁的患者经过基因筛查并被诊断为GSDIb。我们建立了iPSCs，并将这些细胞分化为肝细胞和中性粒细胞，这是GSDIb的主要病理成分。分化为肝细胞的细胞表现出特征性的白蛋白分泌和吲哚菁绿摄取。此外，来自GSDIb代谢异常患者的ipsc来源细胞重现了影响其来源患者的疾病的关键病理特征，如糖原、乳酸、丙酮酸和脂质积累。分化为中性粒细胞的细胞也表现出GSDIb病理。除了中性粒细胞标志物的表达外，我们还发现超氧阴离子产生增加，膜联蛋白V结合增加，caspase-3和caspase-9活化，与GSDIb患者的中性粒细胞一致。这些结果为病理分析和未来治疗的发展提供了有价值的工具。
Glycogen storage disease type Ib (GSDIb) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT), which leads to neutrophil dysfunction. However, the underlying causes of these dysfunctions and their relationship with glucose homeostasis are unclear. Induced pluripotent stem cells (iPSCs) hold a great promise for advances in developmental biology, cell-based therapy and modeling of human disease. Here, we examined the use of iPSCs as a model for GSDIb. In this study, one 2-year-old patient was genetically screened and diagnosed with GSDIb. We established iPSCs and differentiated these cells into hepatocytes and neutrophils, which comprise the main pathological components of GSDIb. Cells that differentiated into hepatocytes exhibited characteristic albumin secretion and indocyanine green uptake. Moreover, iPSC-derived cells generated from patients with GSDIb metabolic abnormalities recapitulated key pathological features of the diseases affecting the patients from whom they were derived, such as glycogen, lactate, pyruvate and lipid accumulation. Cells that were differentiated into neutrophils also showed the GSDIb pathology. In addition to the expression of neutrophil markers, we showed increased superoxide anion production, increased annexin V binding and activation of caspase-3 and caspase-9, consistent with the GSDIb patient's neutrophils. These results indicate valuable tools for the analysis of this pathology and the development of future treatments.