Smith Group

Pluripotent stem cell biology

Pluripotency is the capacity of single cells to generate all cell types of the animal. This cellular plasticity is the foundation of mammalian development. In the embryo pluripotency is dynamic and short-lived, but in vitro pluripotent stem cells can be established and propagated without limit. Pluripotent stem cells can remain in a naive  state. To execute their differentiation potential, naive cells must gain lineage competence, a process termed formative transition. We seek to understand:

  1. how potency and competence are encoded in a dynamic regulatory network of signals, transcription factors and chromatin
  2. how cells transition between states of competence and how fate decisions are made
  3. how the trajectory and regulatory machinery of pluripotency is adapted in different mammals

We currently have an opening for a postdoctoral research fellow to develop and lead a programme of computational and bioinformatics research. You will delineate developmental trajectories, infer gene regulatory networks and dynamics, and model cell fate transition paths in embryos and stem cell-derived embryoids.

You will work mainly with single cell next generation sequencing data from natural and synthetic embryos, stem cell differentiation time courses, and perturbation studies. The study will include comparative analyses between human, non-human primates and other mammals. You will create and implement algorithms, analysis methods and visualisation tools for interrogation of transcriptomic and multimodal ‘omics datasets. You will create mathematical and/or computational models of the pluripotency gene regulatory network and of cell fate transitions that will inform experimental investigation.

You will have the opportunity to supervise project students. In addition to your own research projects, you will advise and support wet lab researchers in the group in design and analysis of ‘omics studies.

Prior knowledge in stem cell or developmental biology is not necessary, but experience in working closely with experimental researchers is essential.

The post is available immediately and funded until 30 April, 2027.

For further details and to apply Click here.

Informal enquiries to: austin.smith@exeter.ac.uk

Further information on the Smith Group: Profile | Living Systems Institute | University of Exeter

PhD Opportunities

University of Exeter PhD Studentship: “The Roadmap of Human Pluripotency”

Supervisors: Prof Austin Smith and Dr Ge Guo, Living Systems Institute

In the early mammalian embryo a group of cells form that have the special property of pluripotency. Pluripotency is the developmental potential of a cell to generate the founder lineages of the embryo: endoderm, mesoderm and ectoderm. The fate of a pluripotent cell is not pre-determined but is decided by regulatory signals. Pluripotent cells taken from embryos can be converted into immortal stem cells in the laboratory by manipulating these signals. In addition, by molecular reprogramming can be used to induce pluripotent stem cells from somatic cells (Takahashi et al., 2007).

Crucially, the competence of pluripotent cells to respond to instructive signals for differentiation changes over time. The first pluripotent cells to emerge in the embryo are termed naïve because they have high potential but are unable to differentiate directly into embryonic lineages. They must first transition to a second stage of pluripotency, termed formative (Smith, 2017), in which competence is gained for lineage differentiation. The molecular machinery underlying competence is poorly understood but is central to the temporospatial pattern of embryonic lineage formation. Knowledge of the competence process will facilitate our ability to direct differentiation in vitro for biomedical applications.      

In human the formative transition takes place over several days, both in culture and in the embryo (Rostovskaya et al., 2019; Tyser et al., 2021). The goal of this PhD project is to build on and complement current investigations characterising the stepwise gain of competence and the underpinning molecular switches. A particular focus will be to derive formative pluripotent stem cells corresponding to different stages of transition and potentially with distinct developmental competencies. The research will be centred around genetic and signalling manipulations of stem cell cultures. Transgenic reporters will be engineered to monitor signalling activity and transcription factor expression in living cells by flow cytometry and advanced microscopy. Accompanying molecular and biochemical analyses will extend to ‘omics studies and gene regulatory network analysis. Depending on the interests of the student there will be collaborative opportunities for mathematical modelling of network dynamics.

Candidates will have a 1st or Upper 2nd class degree (or equivalent) and first-hand experience in laboratory research. You will be enthused by fundamental science, motivated to discover new knowledge, and eager to develop your own ideas.