Physiological and Pharmacological Stimulation for in Vitro Maturation of Substrate Metabolism in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes

Overview

Journal Sci Rep

Specialty Science

Date 2021 Apr 9

PMID 33833285

Citations 20

Authors

Colleen A Lopez

Heba Hussain A A Al-Siddiqi

Ujang Purnama

Sonia Iftekhar

Arne A N Bruyneel

Matthew Kerr

Rabia Nazir

Maria da Luz Sousa Fialho

Sophia Malandraki-Miller

Rita Alonaizan

Fatemeh Kermani

Lisa C Heather

Jan Czernuszka

Carolyn A Carr

Affiliations

Soon will be listed here.

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enable human cardiac cells to be studied in vitro, although they use glucose as their primary metabolic substrate and do not recapitulate the properties of adult cardiomyocytes. Here, we have explored the interplay between maturation by stimulation of fatty acid oxidation and by culture in 3D. We have investigated substrate metabolism in hiPSC-CMs grown as a monolayer and in 3D, in porous collagen-derived scaffolds and in engineered heart tissue (EHT), by measuring rates of glycolysis and glucose and fatty acid oxidation (FAO), and changes in gene expression and mitochondrial oxygen consumption. FAO was stimulated by activation of peroxisome proliferator-activated receptor alpha (PPARα), using oleate and the agonist WY-14643, which induced an increase in FAO in monolayer hiPSC-CMs. hiPSC-CMs grown in 3D on collagen-derived scaffolds showed reduced glycolysis and increased FAO compared with monolayer cells. Activation of PPARα further increased FAO in cells on collagen/elastin scaffolds but not collagen or collagen/chondroitin-4-sulphate scaffolds. In EHT, FAO was significantly higher than in monolayer cells or those on static scaffolds and could be further increased by culture with oleate and WY-14643. In conclusion, a more mature metabolic phenotype can be induced by culture in 3D and FAO can be incremented by pharmacological stimulation.

Citing Articles

Revitalizing the heart: strategies and tools for cardiomyocyte regeneration post-myocardial infarction.

Bois A, Grandela C, Gallant J, Mummery C, Menasche P NPJ Regen Med. 2025; 10(1):6.

PMID: 39843488 PMC: 11754855. DOI: 10.1038/s41536-025-00394-2.

Enhancing Maturation and Translatability of Human Pluripotent Stem Cell-Derived Cardiomyocytes through a Novel Medium Containing Acetyl-CoA Carboxylase 2 Inhibitor.

Correia C, Christoffersson J, Tejedor S, El-Haou S, Matadamas-Guzman M, Nair S Cells. 2024; 13(16.

PMID: 39195229 PMC: 11352932. DOI: 10.3390/cells13161339.

Research Progress towards the Effects of Fatty Acids on the Differentiation and Maturation of Human Induced Pluripotent Stem Cells into Cardiomyocytes.

Gao Z, Zhou F, Mu J Rev Cardiovasc Med. 2024; 24(3):69.

PMID: 39077493 PMC: 11264038. DOI: 10.31083/j.rcm2403069.

Advancing Cardiovascular Drug Screening Using Human Pluripotent Stem Cell-Derived Cardiomyocytes.

Oh J, Kwon O, Park S, Kim J, Lee H, Kim Y Int J Mol Sci. 2024; 25(14).

PMID: 39063213 PMC: 11277421. DOI: 10.3390/ijms25147971.

Switching of hypertrophic signalling towards enhanced cardiomyocyte identity and maturity by a GATA4-targeted compound.

Pohjolainen L, Kinnunen S, Auno S, Kiriazis A, Pohjavaara S, Kari-Koskinen J Stem Cell Res Ther. 2024; 15(1):5.

PMID: 38167208 PMC: 10763434. DOI: 10.1186/s13287-023-03623-x.

References

Ivashchenko C, Pipes G, Lozinskaya I, Lin Z, Xiaoping X, Needle S . Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype. Am J Physiol Heart Circ Physiol. 2013; 305(6):H913-22. DOI: 10.1152/ajpheart.00819.2012. View

Malandraki-Miller S, Lopez C, Al-Siddiqi H, Carr C . Changing Metabolism in Differentiating Cardiac Progenitor Cells-Can Stem Cells Become Metabolically Flexible Cardiomyocytes?. Front Cardiovasc Med. 2018; 5:119. PMC: 6157401. DOI: 10.3389/fcvm.2018.00119. View

Rolfe D, Brown G . Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev. 1997; 77(3):731-58. DOI: 10.1152/physrev.1997.77.3.731. View

Neubauer S . The failing heart--an engine out of fuel. N Engl J Med. 2007; 356(11):1140-51. DOI: 10.1056/NEJMra063052. View

Lopaschuk G, Ussher J, Folmes C, Jaswal J, Stanley W . Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010; 90(1):207-58. DOI: 10.1152/physrev.00015.2009. View

Lehman J, Kelly D . Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart. Clin Exp Pharmacol Physiol. 2002; 29(4):339-45. DOI: 10.1046/j.1440-1681.2002.03655.x. View

Hom J, Quintanilla R, Hoffman D, Bentley K, Molkentin J, Sheu S . The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell. 2011; 21(3):469-78. PMC: 3175092. DOI: 10.1016/j.devcel.2011.08.008. View

Schaaf S, Shibamiya A, Mewe M, Eder A, Stohr A, Hirt M . Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. PLoS One. 2011; 6(10):e26397. PMC: 3197640. DOI: 10.1371/journal.pone.0026397. View

Mummery C, Zhang J, Ng E, Elliott D, Elefanty A, Kamp T . Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ Res. 2012; 111(3):344-58. PMC: 3578601. DOI: 10.1161/CIRCRESAHA.110.227512. View

10.

Chung S, Arrell D, Faustino R, Terzic A, Dzeja P . Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation. J Mol Cell Cardiol. 2010; 48(4):725-34. PMC: 2837789. DOI: 10.1016/j.yjmcc.2009.12.014. View

11.

Chung S, Dzeja P, Faustino R, Perez-Terzic C, Behfar A, Terzic A . Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat Clin Pract Cardiovasc Med. 2007; 4 Suppl 1:S60-7. PMC: 3232050. DOI: 10.1038/ncpcardio0766. View

12.

Mills R, Hudson J . Bioengineering adult human heart tissue: How close are we?. APL Bioeng. 2019; 3(1):010901. PMC: 6481734. DOI: 10.1063/1.5070106. View

13.

Satin J, Itzhaki I, Rapoport S, Schroder E, Izu L, Arbel G . Calcium handling in human embryonic stem cell-derived cardiomyocytes. Stem Cells. 2008; 26(8):1961-72. DOI: 10.1634/stemcells.2007-0591. View

14.

Brito-Martins M, Harding S, Ali N . beta(1)- and beta(2)-adrenoceptor responses in cardiomyocytes derived from human embryonic stem cells: comparison with failing and non-failing adult human heart. Br J Pharmacol. 2008; 153(4):751-9. PMC: 2259205. DOI: 10.1038/sj.bjp.0707619. View

15.

Wilson K, Shen P, Fung E, Karakikes I, Zhang A, InanlooRahatloo K . A Rapid, High-Quality, Cost-Effective, Comprehensive and Expandable Targeted Next-Generation Sequencing Assay for Inherited Heart Diseases. Circ Res. 2015; 117(7):603-11. PMC: 4568077. DOI: 10.1161/CIRCRESAHA.115.306723. View

16.

Yang X, Rodriguez M, Pabon L, Fischer K, Reinecke H, Regnier M . Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J Mol Cell Cardiol. 2014; 72:296-304. PMC: 4041732. DOI: 10.1016/j.yjmcc.2014.04.005. View

17.

Ramachandra C, Mehta A, Wong P, Mai Ja K, Fritsche-Danielson R, Bhat R . Fatty acid metabolism driven mitochondrial bioenergetics promotes advanced developmental phenotypes in human induced pluripotent stem cell derived cardiomyocytes. Int J Cardiol. 2018; 272:288-297. DOI: 10.1016/j.ijcard.2018.08.069. View

18.

Altschul J, Kintigh K, Klein T, Doelle W, Hays-Gilpin K, Herr S . Opinion: Fostering synthesis in archaeology to advance science and benefit society. Proc Natl Acad Sci U S A. 2017; 114(42):10999-11002. PMC: 5651791. DOI: 10.1073/pnas.1715950114. View

19.

Huang J, Yan H, Gao Y, Sun S, He Y, Ding F . Translocation of annexin B1 in response to the stimulation of PMA and ionomycin in cervical cancer cells. Cell Biol Int. 2007; 32(1):121-7. DOI: 10.1016/j.cellbi.2007.08.022. View

20.

Finck B . The PPAR regulatory system in cardiac physiology and disease. Cardiovasc Res. 2006; 73(2):269-77. DOI: 10.1016/j.cardiores.2006.08.023. View