Elsevier

Current Opinion in Cell Biology

Volume 37, December 2015, Pages 68-74
Current Opinion in Cell Biology

Crosstalk between stem cell and cell cycle machineries

https://doi.org/10.1016/j.ceb.2015.10.001Get rights and content

Highlights

  • •

    The pluripotent state has a unique cell cycle relative to somatic cells.

  • •

    Extensive reciprocal crosstalk exists to maintain both pluripotency and a rapid cell cycle.

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    Unique cell cycle maintains pluripotency by inhibiting differentiation.

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    iPS cell reprogramming re-establishes the unique cell cycle of ES cells.

Pluripotent stem cells, defined by an unlimited self-renewal capacity and an undifferentiated state, are best typified by embryonic stem cells. These cells have a unique cell cycle compared to somatic cells as defined by a rapid progression through the cell cycle and a minimal time spent in G1. Recent reports indicate that pluripotency and cell cycle regulation are mechanistically linked. In this review, we discuss the reciprocal co-regulation of these processes, how this co-regulation may prevent differentiation, and how cellular reprogramming can re-establish the unique cell cycle regulation in induced pluripotent stem cells.

Introduction

The proper development of a metazoan organism consisting of a variety of specialized cell types requires the strict co-regulation of the differentiation and cell cycle machineries. As a cell acquires its fully differentiated state, concomitant exit from the cell cycle ensures the integrity of the genome and prevents tumorigenesis. At the opposite end of this spectrum, pluripotent stem cells persist in a state of rapid proliferation. These cells have a unique cell cycle consisting of a short G1 phase, which in part serves to impede differentiation [1••, 2, 3•]. Once the purview of developmental biologists, the fundamental question of how the cell cycle and differentiation are linked has become critical to a broad swath of disciplines including regenerative medicine, cancer biology, and aging. This review will examine recent findings on the dynamic regulation between the pluripotency and cell cycle networks.

Section snippets

Reciprocal regulation of cell cycle and pluripotency networks: pluripotency regulation of the cell cycle

The pluripotent network consists of a core set of transcription factors, including Oct4 (Pou5f1), Sox2, and Nanog, which serve to establish the undifferentiated state and the self-renewing capacity of embryonic stem (ES) cells (reviewed in [4,5]). While it is clear that a major role of these core transcription factors is the activation of the greater pluripotency network [6], an emerging emphasis on crosstalk with the cell cycle machinery has recently been identified (Figure 1 and Table 1).

Reciprocal regulation of cell cycle and pluripotency networks: cell cycle regulation of pluripotency

As the core pluripotency network can control the cell cycle, there are multiple means by which cell cycle regulators control pluripotency (Figure 2). Indeed there are several examples of how the high CDK activity in ES cells may influence the pluripotency network. Loss of CDK1 in human ES cells results in a reduction of pluripotency gene expression, including the core factors OCT4, KLF4, and LIN28, and subsequently increases differentiation [33]. Additionally, these cells show increased DNA

A rapid cell cycle to inhibit differentiation

Not only does the cell cycle play an integral role in the maintenance of pluripotency, but rapid proliferation may also serve to inhibit differentiation, thereby maintaining the undifferentiated state [1••]. By the action of the core pluripotency network, multiple lineage-specific transcription factors are repressed [4, 44]. Similarly, recent advances have indicated that the rapid cycling of ES cells maintains pluripotency by resisting differentiation [3•, 45] and that slowing of the cell cycle

Cell cycle control in the reprogramming of induced pluripotent stem (iPS) cells

When Yamanaka and colleagues first successfully reprogrammed somatic cells to a pluripotent state, they observed that iPS cells grew at a rate similar to ES cells [48]. An integrative genomic analysis of human iPS cell reprogramming indicates that cell cycle genes are upregulated as early as day 5 of reprogramming [49]. Indeed, fully reprogrammed iPS cells acquire the minimal G1 phase typical of ES cells, and accelerated proliferation in the starting cell population aids in the efficiency of

Concluding comments

There are multiple molecular connections between the cell cycle and pluripotency. It appears plausible that these links are critical to establishing and maintaining the undifferentiated state, while setting the stage for later differentiation. The two processes of cell cycle regulation and pluripotency appear to exist in a circular relationship in ES cells where disruption of one will affect the other, resulting in generally two outcomes: cell death and/or differentiation. Indeed there are many

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank members of the Wernig and Sage laboratories for critical comments on the manuscript. This work was supported by the Lucile Packard Foundation for Children's Health (MSK, JS), and the NIH (grant CA114102 to JS). MW is a New York Stem Cell Foundation-Robertson Investigator and a Tashia and John Morgridge Faculty Scholar, and JS is the Harriet and Mary Zelencik Scientist in Children's Cancer and Blood Diseases.

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