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  • Review Article
  • Published:

Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation

Nature Reviews Genetics volume 9, pages 115–128 (2008)Cite this article

Key Points

  • The regulation of stem cell self-renewal is of great biological and medical interest. In particular, adult tissue stem cells must balance stem cell self-renewal and differentiation in order to maintain tissue function and prevent cancer throughout the life of the organism.

  • The cell cycle of embryonic stem (ES) cells is characterized by a reduced (human and primate ES cells) or absent (mouse ES cells) early G1 phase. This may function to reduce or eliminate the dependence of ES cells on mitogen activated protein kinase (MAPK) signalling in order to traverse G1.

  • Many adult stem cells, particularly haematopoietic stem cells, are maintained in the 'resting', or non-cycling, quiescent state. Stem cell quiescence seems to be important for the maintenance of adult stem cell function because most proliferative stimuli, including genetic alterations, induce haematopoietic stem cell exhaustion.

  • Early G1 phase of the cell cycle is an important window during which cells are particularly sensitive to extracellular signals. The few genetic alterations that induce proliferation without causing haematopoietic stem cell exhaustion might do so by avoiding, or facilitating the transition through, early G1.

  • We postulate that embryonic and adult stem cells accomplish self-renewal by reducing or eliminating their dependence on MAPK signalling for the transition through early G1 phase of the cell cycle.

  • The adult stem cell niche might help stem cells self-renew by reducing their exposure to and dependence on MAPK signalling. By inducing stem cell quiescence, the niche pulls the stem cell out of the cell cycle and eliminates the exposure to MAPK signalling in early G1. Secondly, through the presence of signals that can shorten early G1, such as certain morphogens like Wnt, Notch and Hedgehog, the niche reduces the need for MAPK-dependent signalling pathways.

  • Polycomb-mediated silencing of developmental genes seems to be an important mechanism by which self-renewal is maintained by actively suppressing developmental commitment and differentiation. We postulate that typical MAPK-dependent mitogenic stimuli de-repress these genes, thereby promoting developmental commitment.

Abstract

The regulation of stem cell self-renewal must balance the regenerative needs of tissues that persist throughout life with the potential for cell overgrowth, transformation and cancer. Here, we attempt to deconstruct the relationship that exists between cell-cycle progression and the self-renewal versus commitment cell-fate decision in embryonic and adult stem cells. Recent genetic studies in mice have provided insights into the regulation of the cell cycle in stem cells, including its potential modulation by the stem cell niche. Although the dynamics of the embryonic and adult stem cell cycles are profoundly dissimilar, we suggest that shared principles underlie the governance of this important decision point in diverse stem cell types.

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Figure 1: The cell cycle in embryonic stem cells.
Figure 2: Loss of quiescence results in loss of function in adult stem cells.
Figure 3: A possible mechanism linking early G1 transit with commitment or self-renewal.
Figure 4: A model of niche regulation of stem cell proliferation and cell-fate decisions.
Figure 5: Polycomb-mediated silencing of developmental genes imposes self-renewal by actively blocking stem cell differentiation.

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Authors and Affiliations

  1. Massachusetts General Hospital, MGH Center for Regenerative Medicine, Harvard University, 185 Cambridge Street, CPZN Room 4265A, Boston, 02114, Massachusetts, USA

    Keith W. Orford & David T. Scadden

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  1. Keith W. Orford
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Correspondence to David T. Scadden.

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Nature Insight — Stem Cells

Glossary

Embryonic stem cell

ES cell. Cell lines that are derived from early-stage embryos (blastocysts). These cells can differentiate into all somatic lineages (pluripotent) and are capable of self-renewal when grown under the proper culture conditions.

Quiescence

For a cell, quiescence is the property of not being in the cell cycle. Most adult stem cell populations are maintained in this resting state.

Niche

A specific anatomic location composed of cellular and extracellular constituents that regulates how stem cells participate in tissue generation, maintenance and repair. It is a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms.

Morphogens

A small set of secreted, developmental-regulatory signalling molecules that have the unique property of graded activity. That is to say, these molecules tend to form concentration gradients and can have different biological effects at different concentrations.

Neurosphere

A cluster of neurogenic cells that is generated from a single neural stem cell or progenitor cell when they are cultured in a semi-solid medium that contains appropriate neurotrophic growth factors.

Intestinal polyposis

A condition that is characterized by the presence of a multitude of benign polyps within the intestine; although most polyps are benign, these intestinal polyps have the potential to become malignant.

Senescence

The irreversible exit from the cell cycle. This is often caused by passaging through many rounds of cellular proliferation (replicative senescence) or certain forms of cellular stress and is often linked to ageing.

Endosteal niche

A location in the bone marrow where HSCs localize adjacent to osteoblasts. Osteoblasts regulate HSC function through secreted signalling molecules and direct cell–cell contact.

Bone marrow stromal cells

Non-haematopoietic cellular components of the bone marrow that regulate haematopoiesis and constitute part of the HSC niche.

Polycomb group (PcG) proteins

A family of developmentally important proteins that silence gene expression though a chromatin-mediated mechanism. The Polycomb group proteins can function as an epigenetic mechanism that remembers and imposes the transcriptionally silenced state.

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Orford, K., Scadden, D. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 9, 115–128 (2008). https://doi.org/10.1038/nrg2269

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