دورية أكاديمية
Metabolic Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Inhibition of HIF1 alpha and LDHA
| العنوان: | Metabolic Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Inhibition of HIF1 alpha and LDHA |
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| المؤلفون: | Hu, Dongjian, Linders, Annet, Yamak, Abir, Correia, Claudia, Kijlstra, Jan David, Garakani, Arman, Xiao, Ling, Milan, David J., van der Meer, Peter, Serra, Margarida, Alves, Paula M., Domian, Ibrahim J. |
| المصدر: | Hu , D , Linders , A , Yamak , A , Correia , C , Kijlstra , J D , Garakani , A , Xiao , L , Milan , D J , van der Meer , P , Serra , M , Alves , P M & Domian , I J 2018 , ' Metabolic Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Inhibition of HIF1 alpha and LDHA ' , Circulation Research , vol. 123 , no. 9 , pp. 1066-1079 . https://doi.org/10.1161/CIRCRESAHA.118.313249Test |
| سنة النشر: | 2018 |
| المجموعة: | University of Groningen research database |
| مصطلحات موضوعية: | glucose, glycolysis, hypoxia-inducible factor 1, metabolism, myocytes, oxidative phosphorylation, stem cells, HYPOXIA-INDUCIBLE FACTORS, FUNCTIONAL MATURATION, TRANSCRIPTION FACTOR, CANCER METABOLISM, CARDIAC MYOCYTES, FACTOR 1-ALPHA, ADULT, HEART, FORCE, DIFFERENTIATION |
| 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 HIF1 alpha (hypoxia-inducible factor 1 alpha) and its downstream target lactate dehydrogenase A. Conversely, glucose deprivation promoted oxidative phosphorylation and repressed HIF1 alpha. Small molecule inhibition of HIF1 alpha or lactate dehydrogenase A resulted in a switch from aerobic glycolysis to oxidative phosphorylation. Likewise, siRNA inhibition of HIF1 alpha 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 HIF1 alpha/lactate dehydrogenase A inhibition. Conclusions: We show that under standard culture conditions, the HIF1 alpha-lactate dehydrogenase A axis is aberrantly upregulated in hPSC-CMs, preventing their metabolic maturation. Chemical or siRNA inhibition of this pathway ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://research.rug.nl/en/publications/c2e8a168-eee1-4898-8758-fa045e1d8983Test |
| DOI: | 10.1161/CIRCRESAHA.118.313249 |
| الإتاحة: | https://doi.org/10.1161/CIRCRESAHA.118.313249Test https://hdl.handle.net/11370/c2e8a168-eee1-4898-8758-fa045e1d8983Test https://research.rug.nl/en/publications/c2e8a168-eee1-4898-8758-fa045e1d8983Test https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208155Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.61BA3C6A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1161/CIRCRESAHA.118.313249 |
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