Pluripotent stem cells—which can become any cell type in the body—are being watched in real time as they decide whether to stay as they are or transform into something else. The problem is that researchers do not yet understand how the molecular machinery inside these cells makes that choice, which limits the ability to grow pure populations of specific cell types for therapy. This project will track three key proteins—OCT4, SOX2, and NANOG—as they orchestrate the shift from a naïve embryonic stem cell to a more specialised state, and then into germline cells. The work aims to resolve a paradox: why the same proteins that maintain a cell’s ability to become anything also control the formation of eggs and sperm. If successful, the research will reveal the fundamental rules of how cell identity is established and lost. This is fundamental science, not an immediate therapy. But understanding these core principles is what will eventually allow scientists to reliably turn stem cells into transplant-ready tissues, free of tumour-forming cells, for regenerative medicine.
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Cell identity depends on the action of transcription factors and environmental signals that together read the genome. The mechanisms by which cell identity changes during development are of particular interest to fundamental developmental and stem cell biology. In particular, pluripotent cells, which can both self-renew and differentiate to give rise to all lineages in vitro and in vivo, are ideally suited to studying maintenance and changes in cell identity. Application of such knowledge is crucial to the design of robust protocols for in vitro differentiation of cells free from germline tumour-initiating cells for use in cell transplantation and drug discovery. Pluripotent stem cell self-renewal is governed by a pluripotency gene regulatory network centred on the transcription factors OCT4, SOX2 and NANOG. While considerable advances have been made in identifying additional pluripotency gene regulatory network components and in analysing global chromatin binding by transcription factors, these powerful approaches do not tell us how cell decisions are actually made. To better understand the distinction between self-renewal and differentiation we will use precise mechanistic analysis to determine how individual transcription factors affect the operation of the pluripotency gene regulatory network. Pluripotent cells pass through successive states during differentiation. Segregation of germline and somatic lineages occurs from a transitional 'formative' pluripotent state. A key unanswered question is why many pluripotency transcription factors (including OCT4, SOX2 and NANOG) also operate in the germline gene regulatory network and are critical for primordial germ cell (PGC) function. As these cell types have arguably the most radically divergent potencies, this is paradoxical. By studying OCT4, SOX2 and NANOG and by doing so in cells at distinct stages during the transition from naïve pluripotent embryonic stem cells (ESCs) to formative epiblast-like cells (EpiLCs) and from EpiLCs to PGCs, we aim to resolve this paradox and to reveal principles at the very foundation of phenotypic cell identity. Our studies will extend knowledge from the mouse to address germline entry in humans. This proposal has three aims, focused on distinct aspects of pluripotent cell function: 1. How is pluripotency specified and lost in vivo? 2. How do transcription factors act in the maintenance and loss of naïve pluripotency in vitro? 3. What regulatory interactions determine the efficiency of entry to the germline? Delivering the above aims will advance the field by assessing how transcription factors operate as an ensemble to control ESC identity, and by revealing how transcription factors are repurposed at distinct developmental stages. This will break new ground by identifying key mechanisms by which cells exit specific pluripotent states, particularly as they enter the germline, or initiate entry into the primitive streak. Together, this knowledge will provide the insights needed to rigorously command the uniform differentiation of pluripotent cells demanded by future recipients of regenerative medicine strategies.
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