Amino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines.

Amino Acids / metabolism Carcinoma, Hepatocellular / metabolism Cell Differentiation / physiology Cell Line, Tumor Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System / metabolism Female Gene Knockout Techniques Hep G2 Cells Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 3-gamma Hepatocytes / metabolism High-Throughput Screening Assays Homeodomain Proteins Humans Liver Liver Neoplasms / metabolism Male Metabolic Engineering Metabolic Networks and Pathways Middle Aged Pluripotent Stem Cells Stem Cells Transcriptome Tumor Suppressor Proteins

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
13 03 2020
Historique:
received: 12 01 2020
accepted: 17 02 2020
entrez: 15 3 2020
pubmed: 15 3 2020
medline: 14 7 2020
Statut: epublish

Résumé

Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.

Identifiants

DOI: 10.1038/s41467-020-15058-6 PMID: 32170132 PMC: PMC7069944
pubmed: 32170132
doi: 10.1038/s41467-020-15058-6
pii: 10.1038/s41467-020-15058-6
pmc: PMC7069944
doi:

Substances chimiques

Amino Acids 0
FOXA3 protein, human 0
HNF1A protein, human 0
Hepatocyte Nuclear Factor 1-alpha 0
Homeodomain Proteins 0
Tumor Suppressor Proteins 0
prospero-related homeobox 1 protein 0
Hepatocyte Nuclear Factor 3-gamma 135845-91-9
Cytochrome P-450 Enzyme System 9035-51-2
Cytochrome P-450 CYP3A EC 1.14.14.1
CYP3A4 protein, human EC 1.14.14.55

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1393

Références

Hay, M., Thomas, D. W., Craighead, J. L., Economides, C. & Rosenthal, J. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51 (2014).
pubmed: 24406927 doi: 10.1038/nbt.2786
Li, A. P. Accurate prediction of human drug toxicity: a major challenge in drug development. Chem. Biol. Interact. 150, 3–7 (2004).
pubmed: 15522257 doi: 10.1016/j.cbi.2004.09.008
Gomez-Lechon, M. J., Tolosa, L., Conde, I. & Donato, M. T. Competency of different cell models to predict human hepatotoxic drugs. Expert Opin. Drug Metab. Toxicol. 10, 1553–1568 (2014).
pubmed: 25297626 doi: 10.1517/17425255.2014.967680
Godoy, P. et al. Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue. Arch. Toxicol. 90, 2513–2529 (2016).
pubmed: 27339419 pmcid: 5043005 doi: 10.1007/s00204-016-1761-4
March, S. et al. Micropatterned coculture of primary human hepatocytes and supportive cells for the study of hepatotropic pathogens. Nat. Protoc. 10, 2027–2053 (2015).
pubmed: 26584444 pmcid: 5867906 doi: 10.1038/nprot.2015.128
Jakubek, L. M. et al. Hepatic spheroids for long-term tstudies. Appl. Vitr. Toxicol. 2, 185–196 (2016).
doi: 10.1089/aivt.2016.0016
Xiang, C. et al. Long-term functional maintenance of primary human hepatocytes in vitro. Science 364, 399–402 (2019).
doi: 10.1126/science.aau7307
Guo, L. et al. Similarities and differences in the expression of drug-metabolizing enzymes between human hepatic cell lines and primary human hepatocytes. Drug Metab. Dispos. 39, 528–538 (2011).
pubmed: 21149542 pmcid: 3061558 doi: 10.1124/dmd.110.035873
Josse, R. et al. Long-term functional stability of human HepaRG hepatocytes and use for chronic toxicity and genotoxicity studies. Drug Metab. Dispos. 36, 1111–1118 (2008).
pubmed: 18347083 doi: 10.1124/dmd.107.019901
Levy, G. et al. Long-term culture and expansion of primary human hepatocytes. Nat. Biotechnol. 33, 1264–1271 (2015).
pubmed: 26501953 doi: 10.1038/nbt.3377
Anthérieu, S., Chesné, C., Li, R., Guguen-Guillouzo, C. & Guillouzo, A. Optimization of the HepaRG cell model for drug metabolism and toxicity studies. Toxicol. In Vitro 26, 1278–1285 (2012).
Sison-Young, R. L. C. et al. Comparative proteomic characterization of 4 human liver-derived single cell culture models reveals significant variation in the capacity for drug disposition, bioactivation, and detoxication. Toxicol. Sci. 147, 412–424 (2015).
pubmed: 26160117 pmcid: 4583060 doi: 10.1093/toxsci/kfv136
Ulvestad, M. et al. Drug metabolizing enzyme and transporter protein profiles of hepatocytes derived from human embryonic and induced pluripotent stem cells. Biochem. Pharmacol. 86, 691–702 (2013).
pubmed: 23856292 doi: 10.1016/j.bcp.2013.06.029
Gao, X. & Liu, Y. A transcriptomic study suggesting human iPSC-derived hepatocytes potentially offer a better in vitro model of hepatotoxicity than most hepatoma cell lines. Cell Biol. Toxicol. 33, 407–421 (2017).
pubmed: 28144825 doi: 10.1007/s10565-017-9383-z
Roelandt, P., Vanhove, J. & Verfaillie, C. Directed differentiation of pluripotent stem cells to functional hepatocytes. Methods Mol. Biol. 997, 141–147 (2013).
pubmed: 23546753 doi: 10.1007/978-1-62703-348-0_11
Helsen, N. et al. Stem cell-derived hepatocytes: a novel model for hepatitis E virus replication. J. Hepatol. 64, 565–573 (2016).
pubmed: 26626494 doi: 10.1016/j.jhep.2015.11.013
Baxter, M. et al. Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes. J. Hepatol. 62, 581–589 (2015).
pubmed: 25457200 pmcid: 4334496 doi: 10.1016/j.jhep.2014.10.016
Godoy, P. et al. Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J. Hepatol. 63, 934–942 (2015).
pubmed: 26022688 pmcid: 4580233 doi: 10.1016/j.jhep.2015.05.013
Ogawa, S. et al. Three-dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell-derived hepatocytes. Development 140, 3285–3296 (2013).
pubmed: 23861064 pmcid: 4074277 doi: 10.1242/dev.090266
Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).
pubmed: 23823721 doi: 10.1038/nature12271
Nagamoto, Y. et al. The promotion of hepatic maturation of human pluripotent stem cells in 3D co-culture using type I collagen and Swiss 3T3 cell sheets. Biomaterials 33, 4526–4534 (2012).
pubmed: 22445253 doi: 10.1016/j.biomaterials.2012.03.011
Khetani, S. R. & Bhatia, S. N. Microscale culture of human liver cells for drug development. Nat. Biotechnol. 26, 120–126 (2008).
pubmed: 18026090 doi: 10.1038/nbt1361
Nakamori, D. et al. Hepatic maturation of human iPS cell-derived hepatocyte-like cells by ATF5, c/EBPα, and PROX1 transduction. Biochem. Biophys. Res. Commun. 469, 424–429 (2016).
pubmed: 26679606 doi: 10.1016/j.bbrc.2015.12.007
Gu, W. et al. Glycolytic metabolism plays a functional role in regulating human pluripotent stem cell state. Cell Stem Cell 19, 476–490 (2016).
pubmed: 27618217 pmcid: 5055460 doi: 10.1016/j.stem.2016.08.008
Lange, C. et al. Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J. 35, 924–941 (2016).
pubmed: 26856890 pmcid: 5207321 doi: 10.15252/embj.201592372
Guijas, C., Montenegro-Burke, J. R., Warth, B., Spilker, M. E. & Siuzdak, G. Metabolomics activity screening for identifying metabolites that modulate phenotype. Nat. Biotechnol. 36, 316 (2018).
pubmed: 29621222 pmcid: 5937131 doi: 10.1038/nbt.4101
Yanes, O. et al. Metabolic oxidation regulates embryonic stem cell differentiation. Nat. Chem. Biol. 6, 411–417 (2010).
pubmed: 20436487 pmcid: 2873061 doi: 10.1038/nchembio.364
Wanet, A. et al. Mitochondrial remodeling in hepatic differentiation and dedifferentiation. Int. J. Biochem. Cell Biol. 54, 174–185 (2014).
pubmed: 25084555 doi: 10.1016/j.biocel.2014.07.015
Langfelder, P. & Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 9, 559 (2008).
pubmed: 19114008 pmcid: 2631488 doi: 10.1186/1471-2105-9-559
Zhao, D. et al. Promotion of the efficient metabolic maturation of human pluripotent stem cell-derived hepatocytes by correcting specification defects. Cell Res. 23, 157–161 (2013).
pubmed: 23070301 pmcid: 23070301 doi: 10.1038/cr.2012.144
Ordovas, L. et al. Efficient recombinase-mediated cassette exchange in hPSCs to study the hepatocyte lineage reveals AAVS1 locus-mediated transgene inhibition. Stem Cell Rep. 5, 918–931 (2015).
doi: 10.1016/j.stemcr.2015.09.004
Miksys, S. L., Cheung, C., Gonzalez, F. J. & Tyndale, R. F. Human CYP2D6 and mouse CYP2Ds: organ distribution in a humanized mouse model. Drug Metab. Dispos. 33, 1495–1502 (2005).
pubmed: 16033950 doi: 10.1124/dmd.105.005488
Longchamp, A. et al. Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H2S production. Cell 173, 117–129.e14 (2018).
pubmed: 29570992 pmcid: 5901681 doi: 10.1016/j.cell.2018.03.001
Qin, Q. et al. Lisa: inferring transcriptional regulators through integrative modeling of public chromatin accessibility and ChIP-seq data. Genome Biol. 21, 32 (2020).
pubmed: 32033573 pmcid: 7007693 doi: 10.1186/s13059-020-1934-6
Vega, R. B., Huss, J. M. & Kelly, D. P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell. Biol. 20, 1868–1876 (2000).
pubmed: 10669761 pmcid: 85369 doi: 10.1128/MCB.20.5.1868-1876.2000
Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1[agr] transcriptional complex. Nature 450, 736–740 (2007).
pubmed: 18046414 doi: 10.1038/nature06322
Buler, M., Aatsinki, S.-M., Skoumal, R. & Hakkola, J. Energy sensing factors PGC-1alpha and SIRT1 modulate PXR expression and function. Biochem. Pharmacol. 82, 2008–2015 (2011).
pubmed: 21933665 doi: 10.1016/j.bcp.2011.09.006
Cantó, C. & Auwerx, J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20, 98–105 (2009).
pubmed: 19276888 pmcid: 3627054 doi: 10.1097/MOL.0b013e328328d0a4
Bell, C. C. et al. Transcriptional, functional, and mechanistic comparisons of stem cell-derived hepatocytes, HepaRG cells, and three-dimensional human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury. Drug Metab. Dispos. 45, 419–429 (2017).
pubmed: 28137721 pmcid: 5363699 doi: 10.1124/dmd.116.074369
Bell, C. C. et al. Transcriptional, functional and mechanistic comparisons of stem cell-derived hepatocytes, HepaRG cells and 3D human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury. Drug Metab. Dispos. 45, 419–429 (2017).
Aninat, C. et al. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab. Dispos. 34, 75–83 (2006).
pubmed: 16204462 doi: 10.1124/dmd.105.006759
Bell, C. C. et al. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci. Rep. 6, 25187 (2016).
pubmed: 27143246 pmcid: 4855186 doi: 10.1038/srep25187
Sison-Young, R. L. et al. A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity. Arch. Toxicol. 91, 1385–1400 (2017).
pubmed: 27344343 doi: 10.1007/s00204-016-1745-4
Vardhana, S. A. et al. Glutamine independence is a selectable feature of pluripotent stem cells. Nat. Metab. 1, 676–687 (2019).
pubmed: 31511848 pmcid: 6737941 doi: 10.1038/s42255-019-0082-3
Tohyama, S. et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12, 127–137 (2012).
pubmed: 23168164 doi: 10.1016/j.stem.2012.09.013
Grattagliano, I. et al. Mitochondria in chronic liver disease. Curr. Drug Targets 12, 879–893 (2011).
pubmed: 21269263 doi: 10.2174/138945011795528877
Seitz, S. et al. Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity. Nat. Metab. 1, 1009–1026 (2019).
doi: 10.1038/s42255-019-0124-x
Kim, S.-R. et al. Comparative metabolome analysis of cultured fetal and adult hepatocytes in humans. J. Toxicol. Sci. 39, 717–723 (2014).
pubmed: 25242401 doi: 10.2131/jts.39.717
Winnike, J. H. et al. Stable isotope resolved metabolomics of primary human hepatocytes reveals a stressed phenotype. Metabolomics 8, 34–49 (2012).
doi: 10.1007/s11306-011-0284-5
Nakamura, T., Teramoto, H., Tomita, Y. & Ichihara, A. L-proline is an essential amino acid for hepatocyte growth in culture. Biochem. Biophys. Res. Commun. 122, 884–891 (1984).
pubmed: 6383376 doi: 10.1016/0006-291X(84)91173-2
Li, Y., Sattler, G. L. & Pitot, H. C. The effect of amino acid composition of serum-free medium on DNA synthesis in primary hepatocyte cultures in the presence of epidermal growth factor. Vitr. Cell. Dev. Biol. Anim. 31, 867–870 (1995).
doi: 10.1007/BF02634571
Barle, H. et al. The concentrations of free amino acids in human liver tissue obtained during laparoscopic surgery. Clin. Physiol. 16, 217–227 (1996).
pubmed: 8736710 doi: 10.1111/j.1475-097X.1996.tb00570.x
Mallette, L. E., . & Exton, J. H. & Park, C. R. Control of gluconeogenesis from amino acids in the perfused rat liver. J. Biol. Chem. 244, 5713–5723 (1969).
King, W. J. & Krebsbach, P. H. Growth factor delivery: how surface interactions modulate release in vitro and in vivo. Adv. Drug Deliv. Rev. 64, 1239–1256 (2012).
pubmed: 22433783 pmcid: 3586795 doi: 10.1016/j.addr.2012.03.004
Elia, I. & Fendt, S.-M. In vivo cancer metabolism is defined by the nutrient microenvironment. Transl. Cancer Res. 5, S1284–S1287 (2016).
Cantor, J. R. et al. Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell 169, 258–272.e17 (2017).
pubmed: 28388410 pmcid: 5421364 doi: 10.1016/j.cell.2017.03.023
Tardito, S. et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat. Cell Biol. 17, 1556–1568 (2015).
pubmed: 26595383 pmcid: 4663685 doi: 10.1038/ncb3272
Fouraschen, S. M. et al. mTOR signaling in liver regeneration: Rapamycin combined with growth factor treatment. World J. Transplant. 3, 36–47 (2013).
pubmed: 24255881 pmcid: 3832859 doi: 10.5500/wjt.v3.i3.36
Sugiyama, M. et al. p62 promotes amino acid sensitivity of mTOR pathway and hepatic differentiation in adult liver stem/progenitor cells. J. Cell. Physiol. 232, 2112–2124 (2017).
pubmed: 27748507 doi: 10.1002/jcp.25653
Roccio, M., Bos, J. L. & Zwartkruis, F. J. T. Regulation of the small GTPase Rheb by amino acids. Oncogene 25, 657–664 (2006).
pubmed: 16170341 doi: 10.1038/sj.onc.1209106
Wang, C. et al. Autophagic lipid metabolism sustains mTORC1 activity in TSC-deficient neural stem cells. Nat. Metab. 1, 1127–1140 (2019).
doi: 10.1038/s42255-019-0137-5
Han, S. et al. KLF15 regulates endobiotic and xenobiotic metabolism. Nat. Metab. 1, 422–430 (2019).
doi: 10.1038/s42255-019-0054-7
Tirona, R. G. et al. The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat. Med. 9, 220–224 (2003).
pubmed: 12514743 doi: 10.1038/nm815
Pradip, A. et al. High content analysis of human pluripotent stem cell derived hepatocytes reveals drug induced steatosis and phospholipidosis. Stem Cells Int. 2016, 2475631 (2016).
pubmed: 26880940 pmcid: 4736406 doi: 10.1155/2016/2475631
Vanhove, J. et al. H3K27me3 does not orchestrate the expression of lineage-specific markers in hESC-derived hepatocytes in vitro. Stem Cell Rep. 7, 192–206 (2016).
doi: 10.1016/j.stemcr.2016.06.013
Ordovas, L. et al. Rapid and efficient generation of recombinant human pluripotent stem cells by recombinase-mediated cassette exchange in the AAVS1 locus. J. Vis. Exp. 117, 54718 (2016).
Shulman, M. & Nahmias, Y. in Epithelial Cell Culture Protocols (eds, Randell, S. H. & Fulcher, M. L.) 2nd edn, 287–302 (Humana Press, 2013).
Dagda, R. K. et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843–13855 (2009).
pubmed: 19279012 pmcid: 2679485 doi: 10.1074/jbc.M808515200
Elia, I. et al. Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells. Nat. Commun. 8, 15267 (2017).
pubmed: 28492237 pmcid: 5437289 doi: 10.1038/ncomms15267
Nagahashi, M. et al. Interstitial fluid sphingosine-1-phosphate in murine mammary gland and cancer and human breast tissue and cancer determined by novel methods. J. Mammary Gland Biol. Neoplasia 21, 9–17 (2016).
pubmed: 27194029 pmcid: 4947521 doi: 10.1007/s10911-016-9354-7
Wiig, H., Aukland, K. & Tenstad, O. Isolation of interstitial fluid from rat mammary tumors by a centrifugation method. Am. J. Physiol. Heart Circ. Physiol. 284, H416–H424 (2003).
Donato, M. T., Jimenez, N., Castell, J. V. & Gomez-Lechon, M. J. Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes. Drug Metab. Dispos. 32, 699–706 (2004).
pubmed: 15205384 doi: 10.1124/dmd.32.7.699
Lorendeau, D. et al. Dual loss of succinate dehydrogenase (SDH) and complex I activity is necessary to recapitulate the metabolic phenotype of SDH mutant tumors. Metab. Eng. 43, 187–197 (2017).
pubmed: 27847310 doi: 10.1016/j.ymben.2016.11.005

Auteurs

Ruben Boon (R)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium. rboon@mgh.harvard.edu.
ORCID: 0000-0002-9355-674X

Manoj Kumar (M)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.
ORCID: 0000-0002-0572-5786

Tine Tricot (T)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.

Ilaria Elia (I)

Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.

Laura Ordovas (L)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.
Biomedical Signal Interpretation and Computational Simulation (BSICoS) Group, Aragón Institute of Engineering Research, IIS Aragón University of Zaragoza, Aragon I + D Foundation (ARAID), Zaragoza, Spain.
ORCID: 0000-0003-3982-1263

Frank Jacobs (F)

Janssen Research and Development, Beerse, Belgium.

Jennifer One (J)

Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.

Jonathan De Smedt (J)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.

Guy Eelen (G)

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
Laboratory of Angiogenesis and Vascular Metabolism, Center of Cancer Biology, VIB, Leuven, Belgium.
ORCID: 0000-0003-3354-5819

Matthew Bird (M)

Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.

Philip Roelandt (P)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.
Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
Translational Research in GastroIntestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.
Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium.
ORCID: 0000-0003-4475-9089

Ginevra Doglioni (G)

Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.

Kim Vriens (K)

Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.

Matteo Rossi (M)

Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.

Marta Aguirre Vazquez (MA)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.

Thomas Vanwelden (T)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.

François Chesnais (F)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium.
ORCID: 0000-0002-0247-7908

Adil El Taghdouini (A)

Laboratory of Pediatric Hepatology and Cell Therapy, Universit Catholique de Louvain & Cliniques Universitaires St Luc, Institut de Recherche Clinique et Expérimentale (IREC), Brussels, Belgium.

Mustapha Najimi (M)

Laboratory of Pediatric Hepatology and Cell Therapy, Universit Catholique de Louvain & Cliniques Universitaires St Luc, Institut de Recherche Clinique et Expérimentale (IREC), Brussels, Belgium.
ORCID: 0000-0002-7329-9635

Etienne Sokal (E)

Laboratory of Pediatric Hepatology and Cell Therapy, Universit Catholique de Louvain & Cliniques Universitaires St Luc, Institut de Recherche Clinique et Expérimentale (IREC), Brussels, Belgium.

David Cassiman (D)

Hepatology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
ORCID: 0000-0002-6154-0970

Jan Snoeys (J)

Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
ORCID: 0000-0003-3420-424X

Mario Monshouwer (M)

Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.

Wei-Shou Hu (WS)

Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.

Christian Lange (C)

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
Laboratory of Angiogenesis and Vascular Metabolism, Center of Cancer Biology, VIB, Leuven, Belgium.

Peter Carmeliet (P)

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
Laboratory of Angiogenesis and Vascular Metabolism, Center of Cancer Biology, VIB, Leuven, Belgium.
ORCID: 0000-0001-7961-1821

Sarah-Maria Fendt (SM)

Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
ORCID: 0000-0001-6018-9296

Catherine M Verfaillie (CM)

Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium. catherine.verfaillie@kuleuven.be.
ORCID: 0000-0001-7564-4079

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Amino acid levels determine metabolism and...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Carcinome hépatocellulaire › Amino acid levels determine metabolism and...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › Amino acid levels determine metabolism and...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Amino acid levels determine metabolism and...
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questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Amino acid levels determine metabolism and...
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