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Translational control of stem cell function

Nature Reviews Molecular Cell Biology volume 22, pages 671–690 (2021)Cite this article

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Abstract

Stem cells are characterized by their ability to self-renew and differentiate into many different cell types. Research has focused primarily on how these processes are regulated at a transcriptional level. However, recent studies have indicated that stem cell behaviour is strongly coupled to the regulation of protein synthesis by the ribosome. In this Review, we discuss how different translation mechanisms control the function of adult and embryonic stem cells. Stem cells are characterized by low global translation rates despite high levels of ribosome biogenesis. The maintenance of pluripotency, the commitment to a specific cell fate and the switch to cell differentiation depend on the tight regulation of protein synthesis and ribosome biogenesis. Translation regulatory mechanisms that impact on stem cell function include mTOR signalling, ribosome levels, and mRNA and tRNA features and amounts. Understanding these mechanisms important for stem cell self-renewal and differentiation may also guide our understanding of cancer grade and metastasis.

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Fig. 1: Overview of stem cell types and functions.
Fig. 2: Translation and ribosome biogenesis in stem cells.
Fig. 3: mTOR signalling coordinates protein synthesis and ribosome biogensis to stem cell growth, survival and differentiation.
Fig. 4: The differentiation ‘switch’.
Fig. 5: mRNA and tRNA features regulate translation and stem cell function.
Fig. 6: Translational control of tumour grade and metastasis.

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Acknowledgements

The authors thank members of the Green and Watt laboratories for helpful advice and feedback.

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Author notes

  1. These authors contributed equally: James A. Saba, Kifayathullah Liakath-Ali.

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    James A. Saba & Rachel Green

  2. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA

    Kifayathullah Liakath-Ali

  3. King’s College London Centre for Stem Cells and Regenerative Medicine, Guy’s Hospital, London, UK

    Fiona M. Watt

Authors
  1. James A. Saba
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  2. Kifayathullah Liakath-Ali
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  3. Rachel Green
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  4. Fiona M. Watt
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Contributions

J.A.S., K.L.-A., R.G. and F.M.W. contributed to the conceptualization, writing and revisions of the manuscript. J.A.S. and K.L.-A. prepared the figures.

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Correspondence to Rachel Green or Fiona M. Watt.

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Nature Reviews Molecular Cell Biology thanks Vijay Sankaran, Ana Martin-Villalba and Jianlong Wang for their contribution to the peer review of this work.

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Glossary

Self-renewal

A process by which stem cells divide and maintain stemness.

Quiescent

A reversible state in which cells exit the cell cycle but can re-enter it in response to stimuli such as injury to the tissue in which they reside.

Induced pluripotent stem cells

(iPSCs). Somatic cells that are reprogrammed by defined factors to acquire embryonic stem cell-like, pluripotent features.

Dedifferentiation

A process by which terminally or partially differentiated cells revert to less-differentiated cells within the same lineage.

Ribosome biogenesis

(RiBi). A concerted molecular process to build a ribosome involving more than 200 proteins and other factors.

tRNA

A small RNA molecule that links decoding of the mRNA to incorporation of the appropriate amino acid into the nascent peptide strand during translation elongation.

Polysome profiling

An experimental technique in which a cell lysate is separated by density gradient centrifugation and mRNAs associated with multiple ribosomes (polyribosomes or ‘polysomes’) can be fractionated; not to be confused with the sequencing method ribosome profiling.

H/ACA complex

A small nucleolar ribonucleoprotein complex involved in the pseudouridylation of ribosomal RNA.

Cap-dependent translation

Translation initiation by the binding of an mRNA cap protein, usually eukaryotic initiation factor 4E (eIF4E), to a modified guanine structure at the 5′ end of the mRNA. This interaction is required for canonical mRNA translation.

Cell lineages

The developmental paths of a tissue or organ from single or multiple cell types.

Ribosomopathies

Diseases caused by abnormalities in the structure and function of ribosomal proteins or genes encoding ribosomal RNA or genes involved in ribosome biogenesis.

Polysome

Multiple ribosomes loaded onto a single mRNA (‘polyribosome’).

Hypomorphic mutation

A mutation in a gene that confers less function than the wild-type copy of that gene but retains more function than a complete loss-of-function allele.

Ribosome rescue factor

A protein factor that is involved in dissociating the large and small ribosomal subunits of a ribosome stalled on an mRNA (for example, the Pelota–HBS1L complex).

Ribosome profiling

A method to deep sequence ribosome-protected mRNA fragments, also known as ribo-seq.

G-quadruplexes

RNA secondary structures canonically formed by the stacking of planar guanine tetrads and stabilized by Hoogsteen base pairing and a central cation.

Upstream open reading frames

(uORFs). Translatable open reading frame sequences within the 5′ untranslated region of an mRNA.

Integrated stress response

(IRS). An extensive intracellular signalling network activated in response to various stresses to maintain cellular homeostasis.

Codon usage

The use of one codon instead of another one to encode the same amino acid; two codons encoding the same amino acid may be recognized by different tRNAs.

Wobble position

The third nucleotide of a codon in which recognition by the cognate tRNA may occur by certain non-Watson–Crick base pairing.

Mitotic index

A measure of proliferating cells defined as the percentage of cells in mitosis. Used for tumour grading.

Epithelial-to-mesenchymal transition

A process by which epithelial cells lose cell polarity and cell–cell adhesion properties and become mesenchymal-like cells with increased migratory and invasive potential.

Transdifferentiation

The transformation of cells other than stem cells into a different cell type.

Synthetic ribosomes

Engineered artificial small molecules that can mimic ribosome function by synthesizing peptides in a sequence-specific manner.

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Saba, J.A., Liakath-Ali, K., Green, R. et al. Translational control of stem cell function. Nat Rev Mol Cell Biol 22, 671–690 (2021). https://doi.org/10.1038/s41580-021-00386-2

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