Regulatory networks in embryo-derived pluripotent stem cells

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Abstract
Embryo-derived stem cells can be considered archetypal stem cells. Among them, embryonic stem cells (ESCs) are derived at an earlier stage of embryo development than others, such as embryonal carcinoma cells (ECCs) and embryonic germ cells (EGCs). Compared to adult or fetal stem cells, embryo-derived stem cells are easier to identify, to isolate and to use as established cell lines. The golden feature of ESCs is their pluripotency, as defined as the ability to give rise to any derivative of the three primary embryonic germ layers and to germ cells. Pluripotency can be maintained indefinitely if ESCs are cultured under correct conditions, and can be demonstrated in mice when ESCs injected into blastocysts become incorporated in the conceptus and participate in normal development. Notably, disorganized proliferation and tumour formation of ESCs might also occur, regarded here as 'the other side' of pluripotency. ESCs behave normally within a blastocyst but give rise to tumours when transplanted ectopically, for example, under the skin, it therefore implies that exogenous cues have a bearing on cell fate. Whether they do so by priming or by selecting ESC states is not known. Most of the extrinsic and intrinsic regulators that are known to operate in mouse ESCs (for example, LIF and BMP4 extracellular ligands; OCT4, SOX2 and Nanog transcription factors) have a dose-dependent effect on pluripotency. Genes that are required to maintain pluripotency in human ESCs are mostly unknown, with the exception of OCT4. Combinatorial interactions and nonlinear responses, which have been described in mice, compound this situation. The current lack of definitive control over stem-cell fate finds an interesting parallel in the lack of definitive control over nuclei of differentiated cells regaining pluripotency after transfer into oocytes (cloning). An understanding of how pluripotency is secured in ESCs is likely to indicate ways to reinstate pluripotency in somatic cells. The oocyte is the common reactor that is used to reinstate pluripotency on somatic nuclei. However, in the future we might not even need oocytes to reinstate pluripotency, as has been shown for somatic cells fused with ESCs and for bone marrow cells that can become multipotent adult progenitor cells (MAP-C cells) in culture. An understanding of the ESC circuitry might reveal how to achieve phenotypic changes without genetic manipulation of Oct4 and Nanog and other pluripotency-associated genes.