A Glycolytic Solution for Pluripotent Stem Cells

Mlody, Barbara; Prigione, Alessandro

doi:10.1016/j.stem.2016.09.005

Cited by 7 publications

(5 citation statements)

References 10 publications

(17 reference statements)

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“…There is limited understanding of metabolic states in which different types of stem and precursor cells may exist, and the cell intrinsic and extrinsic factors that influence them. Recently, differences in glycolytic rates have also been reported between naive and primed hESCs, indicating that manipulating glycolysis is one way to direct lineage-specific cell fate ( Mlody and Prigione, 2016 , Popovic and Heindryckx, 2017 ). We propose that subthreshold increase in mitochondrial oxidative phosphorylation maintains hESCs in a possible substate of pluripotency that is poised for differentiation.…”

Section: Discussionmentioning

confidence: 99%

OCIAD1 Controls Electron Transport Chain Complex I Activity to Regulate Energy Metabolism in Human Pluripotent Stem Cells

2018

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SummaryPluripotent stem cells (PSCs) derive energy predominantly from glycolysis and not the energy-efficient oxidative phosphorylation (OXPHOS). Differentiation is initiated with energy metabolic shift from glycolysis to OXPHOS. We investigated the role of mitochondrial energy metabolism in human PSCs using molecular, biochemical, genetic, and pharmacological approaches. We show that the carcinoma protein OCIAD1 interacts with and regulates mitochondrial complex I activity. Energy metabolic assays on live pluripotent cells showed that OCIAD1-depleted cells have increased OXPHOS and may be poised for differentiation. OCIAD1 maintains human embryonic stem cells, and its depletion by CRISPR/Cas9-mediated knockout leads to rapid and increased differentiation upon induction, whereas OCIAD1 overexpression has the opposite effect. Pharmacological alteration of complex I activity was able to rescue the defects of OCIAD1 modulation. Thus, hPSCs can exist in energy metabolic substates. OCIAD1 provides a target to screen for additional modulators of mitochondrial activity to promote transient multipotent precursor expansion or enhance differentiation.

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Section: Discussionmentioning

confidence: 99%

OCIAD1 Controls Electron Transport Chain Complex I Activity to Regulate Energy Metabolism in Human Pluripotent Stem Cells

2018

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“…However, the OXPHOS increase in naïve PSCs does not necessarily translate into reduced glycolysis. Naïve PSCs display a bivalent metabolism dependent on both glycolysis and OXPHOS and also exhibit increased glycolytic metabolism . Therefore, the role of mitochondrial activity in pluripotency may be independent from glycolytic regulation.…”

Section: Mitochondrial Metabolism and Dynamics In Stem Cell Homeostasismentioning

confidence: 99%

Mitochondria and the dynamic control of stem cell homeostasis

et al. 2018

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The maintenance of cellular identity requires continuous adaptation to environmental changes. This process is particularly critical for stem cells, which need to preserve their differentiation potential over time. Among the mechanisms responsible for regulating cellular homeostatic responses, mitochondria are emerging as key players. Given their dynamic and multifaceted role in energy metabolism, redox, and calcium balance, as well as cell death, mitochondria appear at the interface between environmental cues and the control of epigenetic identity. In this review, we describe how mitochondria have been implicated in the processes of acquisition and loss of stemness, with a specific focus on pluripotency. Dissecting the biological functions of mitochondria in stem cell homeostasis and differentiation will provide essential knowledge to understand the dynamics of cell fate modulation, and to establish improved stem cell-based medical applications.

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“…Scientists working in different fields (e.g. neural reprogramming, pluripotent stem cell reprogramming and diffentiation) are eagerly studying the roles of metabolism and mitochondria in cell fate specification and conversion (Prigione et al 2014; Ghosh et al 2015; Mlody and Prigione 2016). It seems that the addition of the novel transcriptional activators such as MEF2A and PPARGC1A to GMT and activation of protein kinases such as PKD1, PRKA, CAMK, PRKC and IGF1R significantly increase the maturity of iCMs that can be more similar to adult mature CMs.…”

Section: Discussionmentioning

confidence: 99%

Global transcriptomic analysis of induced cardiomyocytes predicts novel regulators for direct cardiac reprogramming

Talkhabi

Razavi²,

Salari³

2017

J. Cell Commun. Signal.

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Heart diseases are the most significant cause of morbidity and mortality in the world. De novo generated cardiomyocytes (CMs) are a great cellular source for cell-based therapy and other potential applications. Direct cardiac reprogramming is the newest method to produce CMs, known as induced cardiomyocytes (iCMs). During a direct cardiac reprogramming, also known as transdifferentiation, non-cardiac differentiated adult cells are reprogrammed to cardiac identity by forced expression of cardiac-specific transcription factors (TFs) or microRNAs. To this end, many different combinations of TFs (±microRNAs) have been reported for direct reprogramming of mouse or human fibroblasts to iCMs, although their efficiencies remain very low. It seems that the investigated TFs and microRNAs are not sufficient for efficient direct cardiac reprogramming and other cardiac specific factors may be required for increasing iCM production efficiency, as well as the quality of iCMs. Here, we analyzed gene expression data of cardiac fibroblast (CFs), iCMs and adult cardiomyocytes (aCMs). The up-regulated and down-regulated genes in CMs (aCMs and iCMs) were determined as CM and CF specific genes, respectively. Among CM specific genes, we found 153 transcriptional activators including some cardiac and non-cardiac TFs that potentially activate the expression of CM specific genes. We also identified that 85 protein kinases such as protein kinase D1 (PKD1), protein kinase A (PRKA), calcium/calmodulin-dependent protein kinase (CAMK), protein kinase C (PRKC), and insulin like growth factor 1 receptor (IGF1R) that are strongly involved in establishing CM identity. CM gene regulatory network constructed using protein kinases, transcriptional activators and intermediate proteins predicted some new transcriptional activators such as myocyte enhancer factor 2A (MEF2A) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), which may be required for qualitatively and quantitatively efficient direct cardiac reprogramming. Taken together, this study provides new insights into the complexity of cell fate conversion and better understanding of the roles of transcriptional activators, signaling pathways and protein kinases in increasing the efficiency of direct cardiac reprogramming and maturity of iCMs.

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A Glycolytic Solution for Pluripotent Stem Cells

Cited by 7 publications

References 10 publications

OCIAD1 Controls Electron Transport Chain Complex I Activity to Regulate Energy Metabolism in Human Pluripotent Stem Cells

OCIAD1 Controls Electron Transport Chain Complex I Activity to Regulate Energy Metabolism in Human Pluripotent Stem Cells

Mitochondria and the dynamic control of stem cell homeostasis

Global transcriptomic analysis of induced cardiomyocytes predicts novel regulators for direct cardiac reprogramming

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