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José Silva

Biology of induced pluripotency

Naïve pluripotent stem cells are the cell pillar of development as they give rise to all cell types of the body. My lab research is centered on the understanding of the biology underlying the in vitro generation of naïve pluripotent stem cells via nuclear reprogramming. We then make use of the acquired knowledge to also study the principles governing cell identity change, cell potency, epigenetic regulation and the mechanisms regulating developmental processes taking place in naïve pluripotent stem cells.

Our lines of research are:

1- Understanding the fundamental biology of nuclear reprogramming. Nuclear reprogramming is a fundamental process in biology and also a great model system to study cell identity change. Over the years we have identified some of the key factors in this process and their roles and mechanisms and this remains an important line of research in our lab.

Distinct strategies of reprogramming can be successful at generating induced pluripotent stem cells. These include the use of distinct set of reprogramming drivers. By comparing them we also want to identify and define the principles governing cell identity change during reprogramming.

 2- Potential of programing pluripotent stem cells to defined stem cell types of interest. The creation of bonafide pluripotent stem cells from somatic cells by the use of defined factors has opened up the possibility for the generation of any cell type in the petri dish. As a result we are exploring the potential and underlying biology of forward programming pluripotent stem cells into somatic stem cells of interest.  

3- Study the relationship between drivers of reprogramming and epigenetic processes taking place in naïve pluripotent stem cells. Nuclear reprogramming into a naïve pluripotent cell identity involves a radical genomewide transcriptional and epigenetic change. This highlights a potential role of the drivers of nuclear reprogramming regulating these processes. Normal development is somewhat a mirror of reprogramming and we are now asking if the drivers of reprogramming regulate also processes such as the initiation of X-chromosome inactivation which takes place as naïve pluripotent stem cells start to undergo cell differentiation.

Lab members: Lawrence Bates, Yael Costa,  Elsa Sousa, Hannah Stuart, Katsiaryna Maskalenka, Sergey Gladkov



Key publications:

1.Sousa EJ, Stuart HT, Bates LE, Ghorbani M, Nichols J, Dietmann S, Silva JCR.Exit from Naive Pluripotency Induces a Transient X Chromosome Inactivation-like State in Males. Cell Stem Cell (2018). Jun 1;22(6):919-928.e6. doi: 10.1016/j.stem.2018.05.001. Epub 2018 May 24.

2. Santos R, Tosti L, Radzisheuskaya A, Caballero I, Kaji K, Hendrich B, Silva JCR. Mbd3/NuRD facilitates induced pluripotency in a context dependent manner. Cell Stem Cell (2014). Jul 3;15(1):102-10. doi:10.1016/j.stem.2014.04.019.

3. Stuart HT, van Oosten AL, Radzisheuskaya A, Martello G, Miller A, Dietmann S, Nichols J, Silva JCR. NANOG amplifies STAT3 activation and they synergistically induce the naïve pluripotent program. Current Biology. (2014). 24, 1–7, February 3 doi: 10.1016/j.cub.2013.12.040.

4. Radzisheuskaya A, Chia GLB, Santos R, Theunissen TW, Castro LFC, Nichols J, Silva JCR. A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nature Cell Biology. 30 April (2013) doi:10.1038/ncb2742.

5. Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S, Das S ,Levasseur DN, Li Z, Xu M, Reik W, Wang J#, Silva JCR#. Nanog-dependent function of Tet1 and Tet2 in establishment of pluripotency. Nature. (2013) doi:10.1038/nature11925.

6. Radzisheuskaya A, Pasque V, Gillich A, Halley-Stott RP, Panamarova M, Zernicka-Goetz M, Surani MA, Silva JCR. Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. Journal of Cell Science. (2012) Oct 17, doi: 10.1242/jcs.113019

7. van Oosten AL, Costa Y, Smith A, Silva JCR. Jak/Stat3 signalling is sufficient and dominant over antagonistic cues for the establishment of naïve pluripotency. Nature Communications. (2012) May 8;3:817. doi: 10.1038/ncomms1822.

8. Theunissen TW, Costa Y, Radzhisheuskaya A, van Oosten AL, Lavial F, Pain B, CastroLFC, Silva JCR. Reprogramming capacity of Nanog is functionally conserved in vertebrates and resides in a unique homeodomain. Development. (2011) Nov;138(22):4853-65.

9. Theunissen TW, van Oosten AL, Castelo-Branco, G Hall J, Smith A, Silva JCR. Nanog overcomes reprogramming barriers and induces pluripotency in minimal conditions. Current Biology. (2011) Jan 11;21(1):65-71. Epub 2010 Dec 30.

10. Silva J#, Nichols J, Theunissen TW, Guo G, van Oosten AL, Barrandon O, Wray J,Chambers I, Yamanaka S, Smith A#. Nanog is the Gateway to the Pluripotent Ground State. Cell. (2009) Aug 21;138(4):722-37

11. Silva J#, Barrandon O, Nichols J, Theunissen T, Kawaguchi J, Smith A#. Promotion of Reprogramming to Ground State Pluripotency by Signal Inhibition. PLoS Biology. (2008) 6(10): e253 doi:10.1371/journal. pbio.0060253.


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