Jennifer Nichols is accepting applications for PhD students.
Cells with the capacity to produce all adult tissues, including the germ line, can be propagated in culture from the early epiblast in the form of naïve pluripotent embryonic stem (ES) cells. ES cell derivation from mouse embryos is very efficient in defined medium with inhibitors of FGF signalling and GSK3, which together prevent differentiation and promote expansion of the epiblast. Although pluripotent cell lines have been derived from other mammals, these differ from murine ES cells, and are more similar to the primed pluripotent epiblast stem cells obtained from post-implantation mouse embryos. We are currently optimising conditions to capture naive pluripotent stem cells from non-rodent mammalian embryos using a modified version of the mouse ES culture regime.
How the pluripotent lineage is established during development is also an interesting question, which we address using molecular and genetic approaches incorporating mouse lines with specific and inducible deletions in key pluripotency factors. We quantify transcripts using single cell technology and proteins by quantitative immunofluorescence. Conditional deletion mutants provide a valuable system with which to explore the temporal requirement for factors of interest during entry and exit from pluripotency and lineage priming. ES cells maintain a molecular profile closely related to the early epiblast from which they originate. They also retain the capacity to integrate into preimplantation embryos. We exploit this phenomenon to challenge the host embryo to react to the influx of epiblast cells and monitor its response in terms of selective elimination or modification of lineage decisions. Microinjection, live imaging and immunohistochemistry comprise the main tools for this project.
In collaboration with Wolf Reik and members of the Wellcome Trust Strategic Award consortium for single cell technology, we are exploring the molecular properties (currently transcriptome and methylome) of single embryo cells during cell lineage decisions, exit from pluripotency and gastrulation. We wish to understand when and how cells commit to specific tissues, identify lineage-specific molecular motifs and investigate the roles of heterogeneity of expression and cell-cell communication.
Ramiro Alberio (University of Nottingham)
Silvia Muñoz Descalzo (University of Bath)
Berenika Plusa (University of Manchester)
M8, L6, P6, Genetics part II
Takashima Y, Guo G, Loos R, Nichols J, Ficz G, Krueger F, Oxley D, Santos F, Clarke J, Mansfield W, Reik W, Bertone P, Smith A, (2014), Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human, Cell, 158, 1254-69
Boroviak T, Loos R, Bertone P, Smith A, Nichols J, (2014), The ability of inner cell mass cells to self-renew as embryonic stem cells is acquired upon epiblast specification, Nat. Cell Biol., 16, 516-28
Chia G, Muñoz Descalzo S, Kurowski A, Leitch H, Lou X, Mansfield W, Etienne-Dumeau C, Grabole N, Mulas C, Niwa H, Hadjantonakis AK, Nichols J, (2014), Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst, Development, 141, 1001-10
Betschinger J, Nichols J, Dietmann S, Corrin D, Paddison J, Smith A, (2013), Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3, Cell, 153, 335-47
Radzisheuskaya A, Chia G, Santos R, Theunissen TL, Castro F, Nichols J, Silva J, (2013), A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages, Nat. Cell Biol., doi: 10.1038/ncb2742
Leitch H, Nichols J, Humphreys P, Mulas C, Martello G, Lee C, Jones KM, Surani A, Smith A, (2013), Rebuilding Pluripotency from Primordial Germ Cells, Stem Cell reports, 1, 66-78
Morgani S, Canham M, Nichols J, Sharov A, Migueles R, Ko M, Brickman J, (2013), Totipotent embryonic stem cells arise in ground-state culture conditions, Cell Reports, 3, 1945-57
Geti I, Ormiston M, Rouhani F, Toshner M, Movassagh M, Nichols J, Mansfield W, Southwood M, Bradley A, Rana A, Vallier L, Morrell N, (2013), Practical and efficient cellular substrate for the generation of induced pluripotent stem cells from adults: blood-derived endothelial progenitor cells, Stem Cells Transl Med, 1, 12, 855-65
Morgan M, Muller P, Mould A, Newland S, Nichols J, Robertson E, Cooke A, Bikoff E, (2013), The nonconventional MHC class II molecule DM governs diabetes susceptibility in NOD mice, PLoSOne, 8, e56738
Roode M, Blair K, Snell P, Elder K, Marchant S, Smith A, Nichols J, (2012), Human hypoblast formation is not dependent on FGF signalling, Dev. Biol, 361, 358-63 [Faculty 1000 "Must read"]