AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling.
AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling.
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DOI：
10.1186/s13287-023-03554-7
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发表时间：
2023-11-08
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
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作者：
由于低代谢成熟度，使用源自人诱导多能干细胞（hiPSC-CM）的心肌细胞难以对代谢重构的心脏病理结果建模。用AMP活化蛋白激酶（AMPK）活化剂处理hiPSC-CM球，并检查hiPSC-CM成熟特征、分子变化和对病理刺激的反应。用AMPK活化剂处理hiPSC-CM增加了ATP含量、线粒体膜电位和含量、线粒体DNA、线粒体功能和脂肪酸摄取，表明代谢成熟增加。相反，AMPK的敲低抑制hiPSC-CM的线粒体成熟。此外，AMPK激活剂处理的hiPSC-CM具有改善的结构发育和功能特征，包括增强的Ca 2+瞬时动力学和增加的收缩。转录组学、蛋白质组学和代谢组学分析鉴定了AMPK激活剂处理的hiPSC-CM中与成熟心肌细胞的分子特征相关的基因、蛋白质和代谢物的差异表达水平。响应于病理刺激，与未处理的细胞相比，AMPK激活剂处理的hiPSC-CM具有增加的糖酵解和其他病理结果。AMPK激活剂处理的心脏球可以作为一个有价值的模型，以获得新的见解心脏疾病。在线版本包含补充材料，可通过10.1186/s13287-023-03554-7获得。
Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation. hiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli. Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features—including enhanced Ca2+ transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells. AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases. The online version contains supplementary material available at 10.1186/s13287-023-03554-7.
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影响因子：
20.1
作者：
Hu D;Linders A;Yamak A;Correia C;Kijlstra JD;Garakani A;Xiao L;Milan DJ;van der Meer P;Serra M;Alves PM;Domian IJ
通讯作者：
Domian IJ
影响因子：
4.6
作者：
Jha R;Wu Q;Singh M;Preininger MK;Han P;Ding G;Cho HC;Jo H;Maher KO;Wagner MB;Xu C
通讯作者：
Xu C
影响因子：
14.8
作者：
Kempf, Henning;Kropp, Christina;Zweigerdt, Robert
通讯作者：
Zweigerdt, Robert
影响因子：
4.2
作者：
Mayr, Johannes A.;Feichtinger, Rene G.;Sperl, Wolfgang
通讯作者：
Sperl, Wolfgang
影响因子：
7.5
作者：
通讯作者：
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