Sox2 and Klf4 as the Functional Core in Pluripotency Induction without Exogenous Oct4

An, Zhaojun; Liu, Peng; Zheng, Jiashun; Si, Chaozeng; Li, Tianda; Chen, Yang; Ma, Tao; Zhang, Michael Q.; Zhou, Qi; Ding, Sheng

doi:10.1016/j.celrep.2019.10.026

Cited by 39 publications

(39 citation statements)

References 45 publications

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“…In line with the fact that refractoriness to chemotherapy is a hallmark associated with cancer stemness [41][42][43], we could further show that MCT1-driven lactate uptake favors stemness properties. Thus, under glucose restriction and exposure to lactate, PDAC cells are characterized by a greater capacity of colony formation that is seen after their re-exposure to normal glucose supply.…”

Section: Discussionsupporting

confidence: 81%

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells

Sandforth

Ammar

Dinges

et al. 2020

Cancers

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Metabolite exchange between stromal and tumor cells or among tumor cells themselves accompanies metabolic reprogramming in cancer including pancreatic adenocarcinoma (PDAC). Some tumor cells import and utilize lactate for oxidative energy production (reverse Warburg-metabolism) and the presence of these “reverse Warburg“ cells associates with a more aggressive phenotype and worse prognosis, though the underlying mechanisms are poorly understood. We now show that PDAC cells (BxPc3, A818-6, T3M4) expressing the lactate-importer monocarboxylate transporter-1 (MCT1) are protected by lactate against gemcitabine-induced apoptosis in a MCT1-dependent fashion, contrary to MCT1-negative PDAC cells (Panc1, Capan2). Moreover, lactate administration under glucose starvation, resembling reverse Warburg co a phenotype of BxPc3 and T3M4 cells that confers greater potential of clonal growth upon re-exposure to glucose, along with drug resistance and elevated expression of the stemness marker Nestin and reprogramming factors (Oct4, KLF4, Nanog). These lactate dependent effects on stemness properties are abrogated by the MCT1/lactate-uptake inhibitor 7ACC2 or MCT1 knock-down. Furthermore, the clinical relevance of these observations was supported by detecting co-expression of MCT1 and reprogramming factors in human PDAC tissues. In conclusion, the MCT1-dependent import of lactate supplies “reverse Warburg “PDAC cells with an efficient driver of metabostemness. This condition may essentially contribute to malignant traits including therapy resistance.

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Section: Discussionsupporting

confidence: 81%

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells

Sandforth

Ammar

Dinges

et al. 2020

Cancers

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“…4 C,D). Sox2 is a key transcription factor in the maintenance and development of pluripotency 42 , 43 . Stage specific embryonic antigen 1 (SSEA1) is an early marker of the development of pluripotency during the development of induced pluripotent stem cells from mouse embryonic fibroblasts (MEFs) 44 .…”

Section: Resultsmentioning

confidence: 99%

A high throughput screening system for studying the effects of applied mechanical forces on reprogramming factor expression

Lee

Ochoa

Maceda

et al. 2020

Sci Rep

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Mechanical forces are important in the regulation of physiological homeostasis and the development of disease. The application of mechanical forces to cultured cells is often performed using specialized systems that lack the flexibility and throughput of other biological techniques. In this study, we developed a high throughput platform for applying complex dynamic mechanical forces to cultured cells. We validated the system for its ability to accurately apply parallel mechanical stretch in a 96 well plate format in 576 well simultaneously. Using this system, we screened for optimized conditions to stimulate increases in Oct-4 and other transcription factor expression in mouse fibroblasts. Using high throughput mechanobiological screening assays, we identified small molecules that can synergistically enhance the increase in reprograming-related gene expression in mouse fibroblasts when combined with mechanical loading. Taken together, our findings demonstrate a new powerful tool for investigating the mechanobiological mechanisms of disease and performing drug screening in the presence of applied mechanical load.

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“…In order to understand how USP9X may act upon target genes, we searched for transcription factor motifs enrichment using the oPOSSUM web-based platform. We revealed that genes deregulated in Usp9X KD cells were enriched in their promoter for DNA motifs of core pluripotency transcription factors, including KLF4, ZFP281 and MYC ( Supplementary Table 4G-H) [56][57][58]. This suggests that USP9X transcriptional targets are also regulated by pluripotency factors.…”

Section: Usp9x Regulates Pluripotency Transition and Its Depletion Comentioning

confidence: 87%

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

Dieuleveult

Salataj

Ransy

et al. 2020

Preprint

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Embryonic stem cells (ESC) have the unique ability to differentiate into all three germ cell layers. ESC transition through different states of pluripotency in response to growth factor signals and environmental cues before becoming terminally differentiated. Here, we demonstrated, by a multi-omic strategy, that the deubiquitinase USP9X regulates the developmental potential of ESC, and their transition from a naive to a more developmentally advance, or primed, state of pluripotency. We show that USP9X facilitates developmental gene expression and induces modifications of the mitochondrial bioenergetics, including decreased routing of pyruvate towards its oxidation and reduced respiration. In addition, USP9X binds to the pluripotency factor ESRRB, regulates its abundance and the transcriptional levels of a subset of its target genes. Finally, under permissive culture conditions, depletion of Usp9X accelerates cell differentiation in all cell lineages. We thus identified a new regulator of naive pluripotency and show that USP9X couples ESRRB pluripotency transcriptional network and cellular metabolism, both of which are important for ESC fate and pluripotency. Words: 164

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Sox2 and Klf4 as the Functional Core in Pluripotency Induction without Exogenous Oct4

Cited by 39 publications

References 45 publications

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells

A high throughput screening system for studying the effects of applied mechanical forces on reprogramming factor expression

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

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