Metabolic Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Inhibition of HIF1α and LDHA
| العنوان: | Metabolic Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Inhibition of HIF1α and LDHA |
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| المؤلفون: | Ibrahim J. Domian, Annet Linders, Peter van der Meer, Dongjian Hu, Cláudia Correia, David J. Milan, Arman Garakani, Abir Yamak, Margarida Serra, Ling Xiao, Jan David Kijlstra, Paula M. Alves |
| المساهمون: | Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE) |
| المصدر: | Circulation research, 123(9), 1066-1079. LIPPINCOTT WILLIAMS & WILKINS |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Hypoxia-Inducible Factor 1, Physiology, CARDIAC MYOCYTES, 030204 cardiovascular system & hematology, Mitochondria, Heart, hypoxia-inducible factor 1, Indole Alkaloids, Adenosine Triphosphate, 0302 clinical medicine, Myocyte, Myocytes, Cardiac, Glycolysis, Disulfides, TRANSCRIPTION FACTOR, Enzyme Inhibitors, RNA, Small Interfering, glucose, Induced pluripotent stem cell, health care economics and organizations, Sulfonamides, Cell Differentiation, glycolysis, Cell biology, Phenotype, DIFFERENTIATION, Hypoxia-inducible factors, Aminoquinolines, HEART, Stem cell, Cardiology and Cardiovascular Medicine, Signal Transduction, CANCER METABOLISM, Induced Pluripotent Stem Cells, oxidative phosphorylation, FACTOR 1-ALPHA, Oxidative phosphorylation, Biology, Article, Cell Line, FORCE, 03 medical and health sciences, ADULT, stem cells, HYPOXIA-INDUCIBLE FACTORS, Animals, Humans, FUNCTIONAL MATURATION, Transcription factor, L-Lactate Dehydrogenase, myocytes, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Inbred C57BL, 030104 developmental biology, Energy Metabolism, metabolism |
| الوصف: | Rationale: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are a readily available, robustly reproducible, and physiologically appropriate human cell source for cardiac disease modeling, drug discovery, and toxicity screenings in vitro. However, unlike adult myocardial cells in vivo, hPSC-CMs cultured in vitro maintain an immature metabolic phenotype, where majority of ATP is produced through aerobic glycolysis instead of oxidative phosphorylation in the mitochondria. Little is known about the underlying signaling pathways controlling hPSC-CMs’ metabolic and functional maturation. Objective: To define the molecular pathways controlling cardiomyocytes’ metabolic pathway selections and improve cardiomyocyte metabolic and functional maturation. Methods and Results: We cultured hPSC-CMs in different media compositions including glucose-containing media, glucose-containing media supplemented with fatty acids, and glucose-free media with fatty acids as the primary carbon source. We found that cardiomyocytes cultured in the presence of glucose used primarily aerobic glycolysis and aberrantly upregulated HIF1α (hypoxia-inducible factor 1α) and its downstream target lactate dehydrogenase A. Conversely, glucose deprivation promoted oxidative phosphorylation and repressed HIF1α. Small molecule inhibition of HIF1α or lactate dehydrogenase A resulted in a switch from aerobic glycolysis to oxidative phosphorylation. Likewise, siRNA inhibition of HIF1α stimulated oxidative phosphorylation while inhibiting aerobic glycolysis. This metabolic shift was accompanied by an increase in mitochondrial content and cellular ATP levels. Furthermore, functional gene expressions, sarcomere length, and contractility were improved by HIF1α/lactate dehydrogenase A inhibition. Conclusions: We show that under standard culture conditions, the HIF1α-lactate dehydrogenase A axis is aberrantly upregulated in hPSC-CMs, preventing their metabolic maturation. Chemical or siRNA inhibition of this pathway results in an appropriate metabolic shift from aerobic glycolysis to oxidative phosphorylation. This in turn improves metabolic and functional maturation of hPSC-CMs. These findings provide key insight into molecular control of hPSC-CMs’ metabolism and may be used to generate more physiologically mature cardiomyocytes for drug screening, disease modeling, and therapeutic purposes. |
| تدمد: | 1524-4571 0009-7330 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2356eecd962d93c273971dc48c443e47Test https://doi.org/10.1161/circresaha.118.313249Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2356eecd962d93c273971dc48c443e47 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244571 00097330 |
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