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

Autor: Dong Li, Lawrence C. Armand, Fangxu Sun, Hyun Hwang, David Wolfson, Antonio Rampoldi, Rui Liu, Parvin Forghani, Xin Hu, Wen-Mei Yu, Cheng-Kui Qu, Dean P. Jones, Ronghu Wu, Hee Cheol Cho, Joshua T. Maxwell, Chunhui Xu
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Stem Cell Research & Therapy, Vol 14, Iss 1, Pp 1-24 (2023)
Druh dokumentu: article
ISSN: 1757-6512
DOI: 10.1186/s13287-023-03554-7
Popis: 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.
Databáze: Directory of Open Access Journals
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