Comparison of Cardiomyocyte Differentiation Potential Between Type 1 Diabetic Donor- and Nondiabetic Donor-Derived Induced Pluripotent Stem Cells.
Comparison of Cardiomyocyte Differentiation Potential Between Type 1 Diabetic Donor- and Nondiabetic Donor-Derived Induced Pluripotent Stem Cells.
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DOI：
10.3727/096368914x685762
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发表时间：
2015
影响因子：
3.3
通讯作者：
Bai X
中科院分区：
文献类型：
--
作者：
Kikuchi C;Bienengraeber M;Canfield S;Koopmeiner A;Schäfer R;Bosnjak ZJ;Bai X
1型糖尿病（T1 DM）是儿童和青少年中最常见的糖尿病类型。与非糖尿病受试者相比，糖尿病受试者更有可能发生心肌梗死。近年来，诱导多能干细胞（iPSC）受到基础科学家和临床医生越来越多的关注，并因其无限的增殖潜力和分化能力而有望用于心肌再生。然而，尚未研究1型糖尿病供体来源的iPSC（T1 DM-iPSC）的心肌发生。该研究的目的是比较分析非糖尿病供体来源的iPSC（N-iPSC）和T1 DM-iPSC的心肌细胞（CM）分化能力。通过心脏特异性标志物的表达和心脏动作电位的存在来证实分化的CM。由于线粒体生物能量学对CM功能的各个方面都至关重要，因此使用Seahorse细胞外通量分析仪测量细胞外酸化速率和耗氧速率。结果显示，N-iPSC和T1 DM-iPSC表现出类似的分化成自发收缩CM的能力，这些CM表现出结样、心房样或心室样动作电位。分化效率高达90%。此外，从N-iPSC和T1 DM-iPSC分化的CM（分别为N-iPSC-CM和T1 DM-iPSC-CM）显示出1）在糖酵解和线粒体氧化磷酸化水平上良好调节的葡萄糖利用和2）独立于细胞外葡萄糖浓度切换代谢途径的能力。总的来说，我们第一次证明了T1 DM-iPSC可以分化成具有良好调控的葡萄糖利用的功能性CM，如N-iPSC所示，这表明T1 DM-iPSC-CM可能是I型糖尿病患者心肌再生的有希望的自体细胞来源。
Type 1 diabetes mellitus (T1DM) is the most common type of diabetes in children and adolescents. Diabetic subjects are more likely to experience a myocardial infarction compared to non-diabetic subjects. In recent years, induced pluripotent stem cells (iPSCs) have received increasing attention from basic scientists and clinicians and hold promise for myocardial regeneration due to their unlimited proliferation potential and differentiation capacity. However, cardiomyogenesis of type 1 diabetic donor-derived iPSCs (T1DM-iPSCs) has not been investigated yet. The aim of the study was to comparatively analyze cardiomyocyte (CM) differentiation capacity of non-diabetic donor-derived iPSCs (N-iPSCs) and T1DM-iPSCs. The differentiated CMs were confirmed by both expression of cardiac-specific markers and presence of cardiac action potential. Since mitochondrial bioenergetics is vital to every aspect of CM function, extracellular acidification rates and oxygen consumption rates were measured using Seahorse extracellular flux analyzer. The results showed that N-iPSCs and T1DM-iPSCs demonstrated similar capacity of differentiation into spontaneously contracting CMs exhibiting nodal-, atrial-, or ventricular-like action potentials. Differentiation efficiency was up to 90%. In addition, the CMs differentiated from N-iPSCs and T1DM-iPSCs (N-iPSC-CMs and T1DM-iPSC-CMs, respectively) showed 1) the well-regulated glucose utilization at the level of glycolysis and mitochondrial oxidative phosphorylation and 2) the ability to switch metabolic pathways independent of extracellular glucose concentration. Collectively, we demonstrate for the first time that T1DM-iPSCs can differentiate into functional CMs with well-regulated glucose utilization as shown in N-iPSCs, suggesting that T1DM-iPSC-CMs might be a promising autologous cell source for myocardial regeneration in type I diabetes patients.