Metabolome and metaboproteome remodeling in nuclear reprogramming

被引:24
作者
Folmes, Clifford D. L.
Arrell, D. Kent
Zlatkovic-Lindor, Jelena
Martinez-Fernandez, Almudena
Perez-Terzic, Carmen
Nelson, Timothy J.
Terzic, Andre [1 ]
机构
[1] Mayo Clin, Ctr Regenerat Med, Rochester, MN USA
基金
美国国家卫生研究院; 加拿大健康研究院;
关键词
energy metabolism; iPS cells; glycolysis; mitochondria; network biology; oxidative phosphorylation; proteomics; regenerative medicine; systems biology; PLURIPOTENT STEM-CELLS; ENERGY-METABOLISM; SOMATIC-CELLS; HUMAN ES; MITOCHONDRIAL; DIFFERENTIATION; OXYGEN; IDENTIFICATION; FIBROBLASTS; GENERATION;
D O I
10.4161/cc.25509
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Nuclear reprogramming resets differentiated tissue to generate induced pluripotent stem (iPS) cells. While genomic attributes underlying reacquisition of the embryonic-like state have been delineated, less is known regarding the metabolic dynamics underscoring induction of pluripotency. Metabolomic profiling of fibroblasts vs. iPS cells demonstrated nuclear reprogramming-associated induction of glycolysis, realized through augmented utilization of glucose and accumulation of lactate. Real-time assessment unmasked downregulated mitochondrial reserve capacity and ATP turnover correlating with pluripotent induction. Reduction in oxygen consumption and acceleration of extracellular acidification rates represent high-throughput markers of the transition from oxidative to glycolytic metabolism, characterizing stemness acquisition. The bioenergetic transition was supported by proteome remodeling, whereby 441 proteins were altered between fibroblasts and derived iPS cells. Systems analysis revealed overrepresented canonical pathways and interactome-associated biological processes predicting differential metabolic behavior in response to reprogramming stimuli, including upregulation of glycolysis, purine, arginine, proline, ribonucleoside and ribonucleotide metabolism, and biopolymer and macromolecular catabolism, with concomitant downregulation of oxidative phosphorylation, phosphate metabolism regulation, and precursor biosynthesis processes, prioritizing the impact of energy metabolism within the hierarchy of nuclear reprogramming. Thus, metabolome and metaboproteome remodeling is integral for induction of pluripotency, expanding on the genetic and epigenetic requirements for cell fate manipulation.
引用
收藏
页码:2355 / 2365
页数:11
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