Jenny Nichols Research Group

Research in a Nutshell

We study the early stages of mammalian development, from formation of the blastocyst to implantation, gastrulation and the onset of organogenesis. To investigate these processes we employ stem cell-based models whenever possible, but for some studies there is no substitute for the embryo. We collaborate with assisted conception clinics to acquire left over early human embryos, generally deemed unsuitable for embryo transfer, kindly donated to our project with informed consent from anonymous couples undergoing treatment. For more mechanistic analysis, we use mouse embryos, which can be genetically modified to allow investigation of the function of specific genes in development.

We recently derived a bank of stem cell lines from donated human embryos, using protocols modified from our experience with mouse embryos. The lines from different donors allow us to draw general conclusions associated with human developmental processes and not be misled by using a single (potentially abnormal) genetic background. We use these lines to form model embryos, including ‘blastoids’ that replicate the stage just before implantation and ‘gastruloids’ that mimic the posterior end of embryos after implantation undergoing gastrulation and early organogenesis. Around 30-40% of donated embryos exhibit a ‘collapsed’ morphology after thawing. We use these to investigate potential problems causing early pregnancy failure.

Mammalian embryos undergo regulative development, meaning they employ mechanisms to ensure the correct proportions of cells specified for each lineage. Embryonic stem cells (ESCs) can be injected into preimplantation mouse embryos to generate chimaeras, where they can form any tissue in the body. The host embryo utilises various mechanisms to eliminate supernumerary cells before implantation and during gastrulation. Our lab pioneered the use of live imaging during chimaera formation to trace cell competition before implantation and showed that differentiating ESCs are eliminated by apoptosis very early during blastocyst formation, whereas pluripotent cells are retained. We use postimplantation chimaeras as well as whole embryos to investigate the function of specific genes and processes during lineage specification and regulation. The advent of single cell sequencing and multi-omics has enabled us to contribute to creation of large-scale resources to uncover cell signalling mechanisms and interactions that pattern and regulate the developing embryo. These resources are extensively utilised by the community. 

Much of our work is informed using genetically modified mouse lines. We established a system for conditional deletion of Oct4 in the postimplantation epiblast and thereby created a novel model for size regulation and spatial allocation of emerging tissues during gastrulation. We also discovered that embryos lacking STAT3 appear to develop normally, but lag behind their littermates morphologically by around a day. The main cause of this developmental delay appears to be metabolically focussed; single cell RNA sequencing will enable investigation of this phenotype in detail.

Contact

jenny.nichols@ed.ac.uk

Key Publications

1. Ayaka Yanagida, Christopher Revell, Giuliano G. Stirparo, Elena Corujo-Simon, Irene M. Aspalter, Ruby Peters, Henry De Belly, Davide A. D. Cassani, Sarra Achouri, Raphael Blumenfeld, Kristian Franze, Ewa K. Paluch*, Jennifer Nichols* and Kevin J. Chalut* (2022). Cell Surface Fluctuations Regulate Early Embryonic Lineage Sorting. Cell 185 777-793 DOI: 10.1016/j.cell.2022.01.022
2. T.Lohoff, S.Ghazanfar, A.Missarova, N.Koulena, N.Pierson, J.A.Griffiths, E.S.Bardot, C.-H.L.Eng, R.C.V.Tyser, R.Argelaguet, C.Guibentif, S.Srinavas, J.Briscoe, ,B.D.Simons, A.-K.Hadjantonakis, B.Gottgens, W.Reik*, J.Nichols*, L.Cai* and J.C.Marioni* (2021). Highly multiplexed spatially resolved gene expression profiling of mouse organogenesis. Nat. Biotech. 40 74-85 DOI:10.1038/s41587-021-01006-2
3. Stirparo GG, Kurowski A, Yanagida A, Bates LE, Strawbridge SE, Hladkou S, Stuart H, Boroviak TE, and Nichols J (2021). Oct4 Regulates Embryonic Pluripotency via Stat3 Signalling and Metabolic Mechanisms. Proc Natl Acad Sci USA 118 DOI:10.1073/pnas.2008890118
4. Guo, G*, Stirparo, GG*, Strawbridge, SE,* Spindlow, D, Yang, J, Clarke, J, Dattani, A, Yanagida, A, Li, AM, Myers, S Ozel, BN, Nichols, J* and Smith, A* (2021). Human naïve epiblast cells possess unrestricted lineage potential. Cell Stem Cell: 28, 1040-1056 DOI:10.1016/j.stem.2021.02.025
5. Mulas C, Chia, G, Jones, K, Hodgson, A. C, Stirparo, G. G, Nichols, J (2018). Oct4 regulates the embryonic axis and coordinates exit from pluripotency and germ layer specification in the mouse embryo. Development 145 (12) DOI:10.1242/dev.159103
6. Guo G, von Meyenn F, Santos F, Chen Y, Reik W, Bertone P, Smith A and Nichols J (2016). Naïve pluripotent stem cells derived directly from isolated cells of the human inner cell mass. Stem Cell Reports 6, 437-46 DOI:10.1016/j.stemcr.2016.02.005

Collaborations

• Prof Ramiro Alberio, University of Nottingham
• Dr Srinjan Basu, University of Cambridge
• Dr Thomas Burdon, University of Edinburgh
• Prof Ian Chambers, University of Edinburgh
• Prof Bertie Gottgens, University of Cambridge
• Dr Ge Guo, University of Exeter
• Dr Franchesca Houghton, University of Southampton
• Drs Harry Isaacs and Betsy Pownall, University of York
• Dr Hannah Long, University of Edinburgh
• Prof Graziano Martello, University of Padua
• Dr Tristan Rodriguez, Imperial College, London
• Prof Austin Smith, University of Exeter
• Dr Margherita Turco, Friedrich Meischer Institute of Biomedical Research, Basel
• Dr David Turner, University of Liverpool

Partners and Funders

• Cambridge Gastrulation Consortium, Wellcome Trust Collaborative Award
• BBSRC
• MRC