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Review
. 2018 Jul;28(7):551-559.
doi: 10.1016/j.tcb.2018.02.007. Epub 2018 Mar 16.

The Force Is Strong With This One: Metabolism (Over)powers Stem Cell Fate

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Free PMC article
Review

The Force Is Strong With This One: Metabolism (Over)powers Stem Cell Fate

Peng Wei et al. Trends Cell Biol. .
Free PMC article

Abstract

Compared to their differentiated progeny, stem cells are often characterized by distinct metabolic landscapes that emphasize anaerobic glycolysis and a lower fraction of mitochondrial carbohydrate oxidation. Until recently, the metabolic program of stem cells had been thought to be a byproduct of the environment, rather than an intrinsic feature determined by the cell itself. However, new studies highlight the impact of metabolic behavior on the maintenance and function of intestinal stem cells and hair follicle stem cells. This Review summarizes and discusses the evidence that metabolism is not a mere consequence of, but rather influential on stem cell fate.

Keywords: fatty acid oxidation; glycolysis; hair follicle stem cells; intestinal stem cells; pyruvate oxidation; stemness.

Figures

Figure 1
Figure 1. Potential mechanisms by which glucose and fatty acid metabolism might affect stem cell homeostasis
The Wnt/β-Catenin pathway is important in development and in the maintenance and proliferation of epithelial stem cells. In this review, we propose a model wherein Adenomatous polyposis coli (APC), most likely through the Wnt/β-catenin pathway, modulates the expression of MPC1 and MPC2 to alter the cellular metabolic program. This metabolic program then profoundly impacts cell fate, perhaps through feedback regulation on the Wnt/β-Catenin pathway itself. Targets of the Wnt/β-Catenin pathway are also up-regulated in response to fatty acids, possibly through PPARδ-driven gene expression. Potential mechanisms underlying the effects of metabolic program on gene expression and stemness are depicted. Differential redox balance in the cytosol and mitochondria is influenced by the flux of glycolysis, lactate production, pyruvate oxidation and fatty acid oxidation. Redox balance could act through various pathways to modulate gene expression related to stem cell homeostasis. Finally, MPC inhibition also could impair differentiation through epigenetic modifications as MPC deletion decreased H3K4, H3K9 and H3K27 histone acetylation marks. This observation could be explained by a depleted cytosolic acetyl-CoA pool through the reduction of its precursor, citrate, as a result of limited mitochondrial pyruvate. Transporters and enzymes are shown in rounded boxes; transcriptional regulation is depicted by blue arrows; possible relationships are shown in dashed lines; metabolites and histone modifications are shown in regular type.
Figure I
Figure I. Overview of glucose and fatty acid metabolism pathways
TOP. As the end product of glycolysis, pyruvate has two major fates. In the cytosol, it can either be reduced to lactate by lactate dehydrogenase (LDH) or it (and/or its precursors) can be used for biosynthesis. Alternatively, the mitochondrial pyruvate carrier (MPC) can import pyruvate into mitochondria where it can be converted to acetyl-CoA by pyruvate dehydrogenase (PDH). In the cytosol, fatty acyl-CoA synthases (ACS) activate fatty acids by converting them to fatty acyl-CoAs. Transport of fatty acyl-CoA across the mitochondrial membrane requires carnitine palmitoyltransferase 1 (CPT1), carnitine translocase (CAT) and carnitine palmitoyltransferase 2 (CPT2). In the mitochondrial matrix, fatty acyl-CoA is oxidized to acetyl-CoA through β-oxidation. Acetyl-CoA, whether derived from carbohydrates, fatty acids or other fuels, enters the tricarboxylic acid (TCA) cycle to generate NADH and FADH2, which ultimately fuel the electron transport chain (ETC) to produce ATP. The TCA cycle intermediate citrate can be transported to the cytosol, where it can be converted to cytosolic acetyl-CoA by ATP citrate lyase (ACLY). While this process depletes TCA cycle intermediates, they can be replenished through the conversion of pyruvate to oxaloacetate by pyruvate carboxylase (PC). BOTTOM. Decreased pyruvate oxidation caused by low MPC function and high LDH activity or potentially by high fatty acid oxidation can promote stem cell maintenance and function. Similarly, enhanced pyruvate oxidation by high MPC activity or low LDH activity reduces stem cell maintenance and function. Transporters/enzymes are shown in boxes; major metabolic pathways are shown in italics; metabolites are shown in regular type.

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