Bioenergetic Changes during Differentiation of Human Embryonic Stem Cells along the Hepatic Lineage

Hopkinson, Branden M.; Desler, Claus; Kalisz, Mark; Vestentoft, Peter Siig; Rasmussen, Lene Juel; Bisgaard, Hanne Cathrine

doi:10.1155/2017/5080128

Cited by 18 publications

(12 citation statements)

References 25 publications

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“…No significant differences were detected after 168 h compared to controls ( Figure 4G). These results are in accordance with the minor dependence on OXPHOS observed in mature cells [69][70][71].…”

Section: Glycolytic and Oxphos Profiles During Atra-induced Nb4 Diffesupporting

confidence: 90%

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Albanesi

Noguera

Banella

et al. 2020

Cells

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Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.

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Section: Glycolytic and Oxphos Profiles During Atra-induced Nb4 Diffesupporting

confidence: 90%

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Albanesi

Noguera

Banella

et al. 2020

Cells

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“…Our data suggest a role for IRF4-mediated MERTK signaling in CD8 þ T-cell mitochondrial respiration, which is necessary for T CM differentiation and longevity (39,40). We have previously shown that the bioenergetics of even close differentiation stages can differ in their activity of glycolysis and oxidative phosphorylation (41). The downregulation of IRF4 and the change in bioenergetic phenotype demonstrated after anti-PROS1 treatment indicates a shift in differentiation stage of CD8 þ T cells.…”

Section: Discussionmentioning

confidence: 59%

MERTK Acts as a Costimulatory Receptor on Human CD8+ T Cells

Peeters

Dulkeviciute

Draghi

et al. 2019

Cancer Immunology Research

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The TAM family of receptor tyrosine kinases (TYRO3, AXL, and MERTK) is known to be expressed on antigen-presenting cells and function as oncogenic drivers and as inhibitors of inflammatory responses. Both human and mouse CD8 þ T cells are thought to be negative for TAM receptor expression. In this study, we show that T-cell receptor (TCR)-activated human primary CD8 þ T cells expressed MERTK and the ligand PROS1 from day 2 postactivation. PROS1-mediated MERTK signaling served as a late costimulatory signal, increasing proliferation and secretion of effector and memory-associated cytokines. Knockdown and inhibition studies confirmed that this costimulatory effect was mediated through MERTK. Transcriptomic and metabolic analyses of PROS1-blocked CD8 þ T cells demonstrated a role of the PROS1-MERTK axis in differentiation of memory CD8 þ T cells. Finally, using tumor-infiltrating lymphocytes (TIL) from melanoma patients, we show that MERTK signaling on T cells improved TIL expansion and TIL-mediated autologous cancer cell killing. We conclude that MERTK serves as a late costimulatory signal for CD8 þ T cells. Identification of this costimulatory function of MERTK on human CD8 þ T cells suggests caution in the development of MERTK inhibitors for hematologic or solid cancer treatment.

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“…Multiple protocols have been developed to differentiate iPSCs to hepatocyte-like cells, and the resulting cells express hepatic markers and exhibit many functions associated with hepatocytes ( Si-Tayeb et al, 2010 ; Touboul et al, 2010 ). Researchers have previously examined mitochondrial maturation during the formation of iPSC-derived hepatocytes and confirmed an increase of mtDNA copy number, mitochondrial gene expression, cristae structure, and oxygen consumption in iPSC-derived hepatocytes compared with undifferentiated cells ( Yu et al, 2012 ; Hopkinson et al, 2017 ). The high metabolic activity of hepatocytes makes them especially dependent on efficient mitochondrial function to provide ATP, while iPSCs rely largely on glycolysis as the source of energy production ( Folmes et al, 2011 ; Zheng et al, 2016 ).…”

Section: Resultsmentioning

confidence: 89%

A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome

et al. 2018

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SUMMARYPatients with mtDNA depletion syndrome 3 (MTDPS3) often die as children from liver failure caused by severe reduction in mtDNA content. The identification of treatments has been impeded by an inability to culture and manipulate MTDPS3 primary hepatocytes. Here we generated DGUOK-deficient hepatocyte-like cells using induced pluripotent stem cells (iPSCs) and used them to identify drugs that could improve mitochondrial ATP production and mitochondrial function. Nicotinamide adenine dinucleotide (NAD) was found to improve mitochondrial function in DGUOK-deficient hepatocyte-like cells by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 α). NAD treatment also improved ATP production in MTDPS3-null rats and in hepatocyte-like cells that were deficient in ribonucleoside-diphosphate reductase subunit M2B (RRM2B), suggesting that it could be broadly effective. Our studies reveal that DGUOK-deficient iPSC-derived hepatocytes recapitulate the pathophysiology of MTDPS3 in culture and can be used to identify therapeutics for mtDNA depletion syndromes.

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Bioenergetic Changes during Differentiation of Human Embryonic Stem Cells along the Hepatic Lineage

Cited by 18 publications

References 25 publications

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

MERTK Acts as a Costimulatory Receptor on Human CD8+ T Cells

A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome

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