Trends in Cell Biology
Volume 23, Issue 10, October 2013, Pages 484-492
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Review
Metabolism in physiological cell proliferation and differentiation

https://doi.org/10.1016/j.tcb.2013.05.004Get rights and content

Highlights

  • Metabolic changes are involved in cell proliferation and differentiation during embryogenesis and in stem cells.

  • Metabolism is regulated by the signaling pathways that control cell proliferation and differentiation.

  • Metabolites can regulate cell signaling.

Stem and progenitor cells proliferate and give rise to other types of cells through differentiation. Deregulation of this process can lead to many diseases including cancer. Recent evidence suggests that an extensive metabolic reconfiguration of cancer cells allows them to sustain pathological growth by providing anabolic intermediates for biosynthesis. This raises the question of the physiological role of metabolic pathways during normal cell growth and differentiation. Metabolism changes with differentiation, and metabolic pathways may be controlled by the same signals that control cell proliferation and differentiation. However, metabolism could also reciprocally influence these signals. The role of metabolic regulation may extend beyond the provision of intermediates for the biosynthetic needs of proliferation, to affect cell differentiation. Here we bring together a large number of recent studies that support this suggestion and illustrate some of the mechanisms by which metabolism is linked to cell proliferation and differentiation.

Section snippets

The relationship between metabolism and cell fate

Stem and progenitor cells divide and produce different types of cells, a process that requires extensive rearrangements in cellular function. Metabolic demands vary in different cell types, and therefore the activity of pathways that import and allocate nutrients is expected to change during differentiation. How this happens and whether it might be important has not been studied in detail. Indications that metabolic regulation plays major roles during development and in stem cells have emerged,

Cell differentiation involves metabolic changes

A major way to control tissue growth during embryonic development and tissue renewal in adults is through cell differentiation. Terminally differentiated cells often lose their ability to divide and, even among proliferating cells, only a subpopulation of undifferentiated stem cells can undergo long-term self-renewal [10]. Cancer has been proposed to be a disease of differentiation [11], and cancer cells may employ the same transcriptional mechanisms used by stem cells, which are characterized

Signaling pathways that control normal proliferation and differentiation also control metabolism

Multiple signaling pathways affecting both proliferation and differentiation are also implicated in the control of cellular metabolism (Figure 1B and Table 1). The PI3K/AKT/mTOR pathway is a major pathway induced by growth factors, which promotes anabolic pathways and cell proliferation in multiple contexts. It stimulates glucose import and glycolysis through regulation of glucose transporters and glycolytic enzymes, promotes fatty acid synthesis through SREBPs, and protein synthesis through

The role of metabolic adaptations in cellular differentiation

The function of metabolic rewiring, particularly of aerobic glycolysis, in enhancing biosynthesis to satisfy the needs of proliferation has gathered widespread supporting evidence [1]. Nevertheless, a variety of recent results suggest that there might be additional functions of aerobic glycolysis in the regulation of differentiation. Inhibition of glycolysis attenuates the reprogramming of dividing somatic cells to induced pluripotent stem cells without affecting cell proliferation 16, 44.

Molecular mechanisms that link metabolism to regulation of differentiation: control of signaling pathways and epigenetic modifications by metabolites

Metabolic networks are controlled by signaling pathways (Figure 1B). However, the converse is also true, and often the same pathways that influence metabolism are themselves regulated by metabolic products (Figure 1, Figure 2). AMPK is activated by energetic stress through binding of ADP and AMP, and by phosphorylation by LKB1 [40], and promotes catabolic while inhibiting anabolic reactions. In response to glucose restriction in cultured myoblasts, AMPK activation promotes NAD+ biosynthesis,

Concluding remarks

Despite numerous advances in understanding cancer metabolism 2, 3, 4, the role of metabolic adaptations during normal growth is not well understood. Metabolic changes accompany cell differentiation, and they might be brought about by signals that determine cell fate. Conversely, metabolic pathways can influence these signals. As the fundamental links between metabolism and signaling are being mapped out, the next major challenge will be to establish how these cellular mechanisms operate during

Acknowledgments

We are grateful to the Royal Commission for the Exhibition of 1851 (M.A.) and the Wellcome Trust (W.A.H.) for support. We thank S. He and E. Piskounova for comments on the manuscript.

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