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 short-lived, but in vitro pluripotent stem cells may be propagated without limit. Pluripotent stem cells may remain in a naive undifferentiated state while retaining the ability to differentiate into multiple cell lineages. Our aims are:
- to understand the conditions required to capture pluripotency from the early embryo;
- to define the regulatory network dynamics that confer broad developmental competence;
- to elucidate and take control of the mechanisms that direct different cell fates.
We are currently recruiting for a Postdoctoral Research Fellow with expertise in molecular developmental and stem cell biology and for a Bioinformatician/Computational Biologist.
Further information on the Smith Group: Profile | Living Systems Institute | University of Exeter
LSI-funded PhD studentship: “Fusing experiments and mathematical models to understand human embryo development”
Supervisors: Associate Prof Marc Goodfellow and Prof Austin Smith Living Systems Institute
A project description and the application link to follow soon.
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.
Application details to follow soon.