AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling

• Type of Material: Article
• Authors: Dong Li, Emory University; Lawrence C. Armand, Emory University; Fangxu Sun, Georgia Institute of Technology; Hyun Hwang, Emory University; David Wolfson, Emory University; Antonio Rampoldi, Emory University; Rui Liu, Emory University; Parvin Forghani Esfahani, Emory University; Xin Hu, Emory University; Wen-Mei Yu, Emory University; Cheng-Kui Qu, Emory University; Dean P Jones, Emory University; Ronghu Wu, Georgia Institute of Technology; Hee Cho, Emory University; Joshua Maxwell, Emory University; Chunhui Xu, Emory University
• Language: English
• Date: 2023-11-08
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © 2023, The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1186/s13287-023-03554-7
• Title of Journal or Parent Work: Stem Cell Research & Therapy
• Volume: 14
• Start Page: 322
• Grant/Funding Information: This study was supported in part by grants from the National Institutes of Health (R01HL136345 and R01AA028527) and the National Science Foundation and the Center for Advancement of Science in Space (CBET 1926387).
• Keywords: Pathological modeling; Metabolic regulation; Maturation; Stem cells; AMPK; Cardiomyocytes
• Research Categories: Health Sciences, Pharmacology; Biology, Cell

Abstract

Background 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. Methods 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. Results 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. Conclusion AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.