Metabolism in pluripotency: Both driver and passenger?

Dahan, Perrine; Lu, Vivian; Nguyen, Reginald T; Kennedy, Stephanie A.L.; Teitell, Michael A.

doi:10.1074/jbc.tm117.000832

Cited by 67 publications

(48 citation statements)

References 100 publications

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“…In line with this observation, using genome-wide immunoprecipitation-based techniques, BMAL1 has been shown to target genes related to cellular metabolism in somatic cells (Hatanaka et al, 2010;Wu et al, 2017;Reinke & Asher, 2019), therefore pointing to a potential direct regulation of metabolic genes by BMAL1 through chromatin binding. Although until recently changes in metabolism were thought to be a consequence of differentiation, it is now clear that metabolism plays an active role in cell fate commitment, mainly by modifying the epigenome, which can in turn regulate pluripotency, differentiation, and somatic cell reprogramming (Dahan et al, 2019). Pluripotent stem cells favour glycolysis over OXPHOS, thus both reducing potential DNA damage by ROS, whereas increasing the amount of available intermediate metabolites for biosynthesis of lipids and nucleotides.…”

Section: Discussionmentioning

confidence: 99%

“…Collectively, our results show that BMAL1 contributes to the proper transcriptional landscape regulation of pluripotent cells and that its depletion leads to the deregulation of metabolism-related transcriptional pathways. Changes in metabolic activity are closely linked to the exit of pluripotency, partly by influencing the epigenome during cell commitment (Cliff & Dalton, 2017;Dahan et al, 2019). Thus, we speculated that Bmal1 depletion can alter early cell differentiation potential through changes in the expression of metabolic gene networks that govern the balance between glycolytic and oxidative phosphorylation (OXPHOS) activity.…”

Section: Bmal1 Supports Glycolytic Metabolism In Escsmentioning

confidence: 99%

“…Collectively, these findings show that BMAL1 is required for proper metabolic dynamics and mitochondrial function of pluripotent ESCs. Taking into account that the balance between glycolysis and OXPHOS is critical for modulating the differentiation potential of pluripotent cells Cliff & Dalton, 2017;Zhang et al, 2018;Dahan et al, 2019), we tested whether reducing OXPHOS activity in Bmal1 KO ESCs could restore the proper expression of lineage specification markers during in vitro differentiation. For this purpose, we used an early differentiation in vitro assay to rapidly induce the expression of genes involved in mesendoderm (ME) lineage choice (Thomson et al, 2011).…”

Section: Bmal1 Supports Glycolytic Metabolism In Escsmentioning

confidence: 99%

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BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells

et al. 2020

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BMAL1 is essential for the regulation of circadian rhythms in differentiated cells and adult stem cells, but the molecular underpinnings of its function in pluripotent cells, which hold a great potential in regenerative medicine, remain to be addressed. Here, using transient and permanent loss-of-function approaches in mouse embryonic stem cells (ESCs), we reveal that although BMA L1 is dispensable for the maintenance of the pluripotent state, its depletion leads to deregulation of transcriptional programs linked to cell differentiation commitment. We further confirm that depletion of Bmal1 alters the differentiation potential of ESCs in vitro. Mechanistically, we demonstrate that BMAL1 participates in the regulation of energy metabolism maintaining a low mitochondrial function which is associated with pluripotency. Loss-offunction of Bmal1 leads to the deregulation of metabolic gene expression associated with a shift from glycolytic to oxidative metabolism. Our results highlight the important role that BMAL1 plays at the exit of pluripotency in vitro and provide evidence implicating a non-canonical circadian function of BMAL1 in the metabolic control for cell fate determination.

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Section: Discussionmentioning

confidence: 99%

Section: Bmal1 Supports Glycolytic Metabolism In Escsmentioning

confidence: 99%

Section: Bmal1 Supports Glycolytic Metabolism In Escsmentioning

confidence: 99%

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BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells

et al. 2020

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“…It is to be noted that the TGFβ pathway is important for pluripotency due to its direct modulation of expression of Nanog (Xu et al, 2008). The increased expression of genes related to the glycolytic pathway in ARPE-19 cells, upon SPIR treatment, reflects the pluripotent state of these cells under these conditions, since aerobic glycolysis supports the maintenance of the pluripotent state by maintaining histone acetylation and the associated open chromatin structure of PSCs (Moussaieff et al, 2015;Gu et al, 2016;Folmes et al, 2011;Guda et al, 2018;Cliff et al, 2017, Dahan et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Sustained exposure to trypsin causes cells to transition into a state of reversible stemness that is amenable to transdifferentiation

Sharma

Kumar

Sharma

et al. 2019

Preprint

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During cell culture, trypsin, a serine protease, is applied to cells for 5-10 minutes to separate them from each other and from the underlying substratum so that they can be transferred to a different vessel, for re-plating, after growth medium containing 10 % serum has been added to the cells, in a well-known technique known as 'passaging'. The serum in the growth medium contains alpha-1 antitrypsin, which is a potent inhibitor of trypsin, elastase and other serine proteases.Although what is used is bovine serum in which levels of proteins could be different from levels seen in humans, normal human serum contains A1AT (> 1 mg/ml; > ~18 µmol/L) as well as trypsin itself (< 460 ng/ml, or ~0.02 µmol/L), with the former in a ~900-fold molar excess over the latter. Thus, it may be assumed there is also enough A1AT in the bovine serum added during passaging, to neutralize the trypsin (~100 μM) present in the small volume of trypsin-EDTA solution used to separate cells. What are the consequences of not adding serum, when growth medium is added, or of maintaining cells for a few tens of hours in the presence of trypsin, in a serum-free growth medium? What does such sustained exposure to trypsin during cell culture do to cells? More generally, what are the responses of cells within an organism to the balance of trypsin and A1AT in the serum that bathes them constantly? We know that excesses and deficiencies in the levels of either trypsin or A1AT are associated with disease. We know that cellular metabolism can be influenced through signaling involving protease activated membrane GPCR receptors (PAR1-4). In particular, we know of a receptor called PAR2, which is specifically activated by trypsin, expressed by cells at baseline levels, and upregulated through some feedback involving trypsin-activation. We also know that cells at sites of injury or inflammation produce and secrete trypsin, and that this trypsin can act locally upon cells in a variety of ways, all of which have probably not yet been elucidated. Here, we show that sustained exposure to trypsin induces cells to de-differentiate into a stem-like state. We show that if serum is either not added at all, or added and then washed away (after confluency is attained), during cell culture, all cells exposed to exogenously-added trypsin undergo changes in morphology, transcriptome, secretome, and developmental potential, and transition into a state of stemness, in minimal essential medium (MEM). Regardless of their origins, i.e., independent of whether they are derived from primary cultures, cell lines or cancer cell lines, and regardless of the original cell type used, exposure to trypsin (~10 µM; ~250 µg/ml) at a concentration 10-fold lower than that used to separate cells during passaging (~100 μM), over a period of 24-48 hours, causes cells to (1) become rounded, (2) cluster together, (3) get arrested in the G0/G1 stage of the cell cycle, (4) display increased presence of 5-hydroxymethyl cytosine in their nuclei (indicative of reprogramming), (5) display increased...

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“…By contrast, the roles of cellular lipids and AlbuMAX in hPSCs have been well described. Some studies have demonstrated that AlbuMAX and cellular lipids, such as prostaglandin E2, linoleic acid, and fatty acid synthesis are essential for stem cell pluripotency (Garcia-Gonzalo and Izpisua Belmonte, 2008; Kim et al, 2009;Wang et al, 2017;Dahan et al, 2019). Moreover, a recent report has suggested that lipid deprivation in E8 based-cell culture media could promote a naïve-to-primed intermediate state via changes in the epigenetic landscape, naïve protein expression levels, and mitochondrial morphology (Cornacchia et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

TGFβ superfamily signaling regulates the state of human stem cell pluripotency and competency to create telencephalic organoids

Watanabe

Haney

Vishlaghi

et al. 2019

Preprint

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Telencephalic organoids generated from human pluripotent stem cells (hPSCs) are emerging as an effective system to study the distinct features of the developing human brain and the underlying causes of many neurological disorders. While progress in organoid technology has been steadily advancing, many challenges remain including rampant batch-to-batch and cell lineto-cell line variability and irreproducibility. Here, we demonstrate that a major contributor to successful cortical organoid production is the manner in which hPSCs are maintained prior to differentiation. Optimal results were achieved using fibroblast-feeder-supported hPSCs compared to feeder-independent cells, related to differences in their transcriptomic states.Feeder-supported hPSCs display elevated activation of diverse TGFβ superfamily signaling pathways and increased expression of genes associated with naïve pluripotency. We further identify combinations of TGFβ-related growth factors that are necessary and together sufficient to impart broad telencephalic organoid competency to feeder-free hPSCs and enable reproducible formation of brain structures suitable for disease modeling. HIGHLIGHTS• hPSC maintenance conditions influence outcomes in cortical organoid formation • Identification of an intermediate pluripotency state optimal for cortical organoids • Feeder support involves activation of diverse TGFβ signaling pathways • The organoid-promoting effects of feeders can be mimicked by a TGFβ factor mixture 3 KEYWORDS brain organoid, neurogenesis, neural stem cell, embryonic stem cell, pluripotent stem cell, differentiation, neural development, stem cell heterogeneity, pluripotency, cerebral cortex, ganglionic eminence, hippocampus 4

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Metabolism in pluripotency: Both driver and passenger?

Cited by 67 publications

References 100 publications

BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells

BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells

Sustained exposure to trypsin causes cells to transition into a state of reversible stemness that is amenable to transdifferentiation

TGFβ superfamily signaling regulates the state of human stem cell pluripotency and competency to create telencephalic organoids

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