Stochastic and deterministic processes in cell fate decisions

During development cells undergo fate changes. A close look to this process reveals an intermediate state in which cells express markers of both, the state of origin and the state of destination. We have called these states 'transition states' and can be observed as intermediaries in the emergence of tissues and organs. The self replication of these transition states provides a framework to understand the origin of adult stem cell populations (see Muñoz-Descalzo, S., Navascues, J. and Martinez Arias, A. 2012 Wnt-Notch signalling: an integrated mechanism regulating transitions between cell states. Bioessays 34, 110-118).

Studies of transcriptional noise in bacteria have provided us with a paradigm to think about the ‘transition state’ (Martinez Arias and Hayward, 2006; Muñoz Descalzo et al. 2011). This work revealed that in circumstances of low transcriptional activity of state determinants, the phenotype of a bacteria is the result of stochastic processes which can be modulated externally. With these ideas in mind and the notion that a stem cell population is a captured transition state (see Fig. 1), we turned our attention to mouse Embryonic Stem (ES) cells – clonal populations of cultured cells derived from preimplantation embryos characterized by their ability to give rise to all cell types of an embryo in culture or in vivo. ES cells are driven by a small and accountable network of transcription factors and allow for controlled experiments at the single cell level which we are using to try to link molecular processes to cellular behaviour.

We have spent some time understanding the molecular basis of pluripotency under the assumption that it is not only about the components of networks but about their dynamics and are interested in how stochastic processes at the molecular level are transformed into deterministic processes at the level of populations of cells. We do this through a number of projects whose common theme is the transition from one state to another.

  • The exit from and restriction of mouse Embryonic Stem cells from pluripotency.
  • The decision of a differentiating cell to become either neuroectoderm or endomesoderm.
  • The interconversion between Embryonic (ES) and Primitive Endoderm (XEN) stem cells in culture

Our work makes use of single cell analysis at the level of transcripts and proteins as well as live imaging and analysis of gene expression.

References

Chalancon G, Ravarani CN, Balaji S, Martinez-Arias A, Aravind L, Jothi R, Babu MM. (2012) Interplay between gene expression noise and regulatory network architecture. Trends in Genet. 28, 221-232.

Martinez Arias, A. and Hayward, P. (2006) Filtering transcriptional noise during development: concepts and mechanisms. Nature Reviews Genetics 7, 34-44.

Martinez Arias, A. and Brickman, J. (2011) Gene expression heterogeneities in embryonic stem cell populations: origin and function. Curr.Op. in Cell Biology 23, 650-656.

Muñoz Descalzo, S., de Navascues, J and Martinez Arias, A. (2012) Wnt/Noch signaling: an integrated mechanism regulating transitions between cell states. Bioessays 34, 110-118.

Trott, J., Hayashi, K., Surani, A., Babu, M. and Martinez Arias, A. (2012) Dissecting ensemble networks in ES cell populations reveals micro-heterogeneity underlying pluripotency. Molecular Biosystems 8, 744-752.