Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes

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 betwe...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/620b82f11a04444ebfe740c6e09d998a
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spelling	oai:doaj.org-article:620b82f11a04444ebfe740c6e09d998a2021-12-02T14:37:15ZPhysiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes10.1038/s41598-021-87186-y2045-2322https://doaj.org/article/620b82f11a04444ebfe740c6e09d998a2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87186-yhttps://doaj.org/toc/2045-2322Abstract 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.Colleen A. LopezHeba Hussain A. A. Al-SiddiqiUjang PurnamaSonia IftekharArne A. N. BruyneelMatthew KerrRabia NazirMaria da Luz Sousa FialhoSophia Malandraki-MillerRita AlonaizanFatemeh KermaniLisa C. HeatherJan CzernuszkaCarolyn A. CarrNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes
description	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.
format	article
author	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
author_facet	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
author_sort	Colleen A. Lopez
title	Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes
title_short	Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes
title_full	Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes
title_fullStr	Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes
title_full_unstemmed	Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes
title_sort	physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/620b82f11a04444ebfe740c6e09d998a
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Physiological and pharmacological stimulation for in vitro maturation of substrate metabolism in human induced pluripotent stem cell-derived cardiomyocytes

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