Jose silva crop 2012

Dr José Silva

Biology of Induced Pluripotency

Email: jcs64@cscr.cam.ac.uk

Laboratory Location:

Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Silva Lab Members

Visit the group external website

Departmental Affiliation:

José is a Wellcome Trust Research Fellow and a member of the Department of Biochemistry, University of Cambridge.

 

Co-workers:

• Yael Costa  • Aliaksandra Radzisheuskaya • Chibeza Agley (joint with Kevin Chalut's lab) • Lawrence Bates  • Rodrigo Santos  • Moyra Lawrence  • Hannah Stuart

Education

José received his first degree in Biology from the University of Porto, in Portugal. He joined the GABBA graduate program from University of Porto and then went on to do his PhD studies at Imperial College under the supervision of Professor Neil Brockdorff on heritable silencing mechanisms during mouse development.

Professional History

In 2003 and following his PhD, José moved to Professor Austin Smith's laboratory at the University of Edinburgh as an EMBO post-doctoral fellow to investigate factors involved in nuclear reprogramming. This work has led to the identification of Nanog as the first defined gene with nuclear reprogramming capacity in the conversion of a somatic cell into pluripotency.

In 2008 José started as a group leader at the CSCR investigating the underlying biology of the process of induced pluripotency. His work was initially supported by a Next Generation Award (2008) and subsequently by a Wellcome Trust Career Development Fellowship Award (2009).


Lab Information

The aim of our lab is to understand the underlying biology of the conversion of a somatic epigenome back into a pluripotent epigenome, a process known as induced pluripotency. We are particularly interested in determining the molecular mechanisms by which the key players in this process work. Fully understanding induced pluripotency and better characterising iPS and ES cells is indispensible before these can be used in biomedical applications


Sources of funding: Wellcome Trust • Next Generation Award • Isaac Newton Trust

 

Vacancies!!!!!!

Research Assistant Position

A research assistant position will be available in the Silva lab from the 1st July. For further details please check the advert here and the University of Cambridge jobs listing page:

http://www.jobs.cam.ac.uk/job/3595

 

 

J. Silva Fig. 1

A colony of stem cells reprogrammed to a pluripotent state from adult brain cells. Inhibitors of the Mek/Erk and GSK3 pathways (2i) in the absence of serum promote the generation of induced pluripotent stem (iPS) cell colonies, shown here. These cells show expression of a pluripotency reporter (green) and reactivation of the silent X chromosome, as demonstrated by the lack of the nuclear red staining body (trimethyl H3K27). For comparison, a cluster of non-reprogrammed cells (non-green) displaying a silent X chromosome (red nuclear body) is shown in the bottom right-hand corner.

J. Silva Fig. 2

Requirement for Nanog in induced pluripotency. The process of induction of pluripotency, for which Nanog is crucial, has three phases. The initiation phase comprises the transduction of somatic cells with reprogramming transgenes Oct4, Klf4 and cMyc. This results in the appearance of a proliferative cell type (pre-iPS) where downregulation of genes from the original cell and expression of some markers of pluripotency occurs. This phase does not require the expression of Nanog. Pre-iPS cells are dependent on the continuous expression of transgenes, are not pluripotent and their exposure to 2i/LIF culture conditions leads to the generation of induced pluripotent stem (iPS) cells. This event marks the establishment phase and Nanog is required for its completion. In the maintenance phase, the last in the process of induction of pluripotency, Nanog is no longer required and can be deleted without compromising self-renewal or the ability of Nanog null iPS cells to contribute to the adult animal.

J. Silva Fig. 5

The image highlights the requirement of Nanog in the early embryo. Whereas the wild type embryo (left) exhibits an inner cell mass (yellow/orange colour) where the pluripotent cells of the embryo are present, the Nanog null embryo fails to generate this population (collaborative work with Dr Jennifer Nichols and Prof. Austin Smith).

PhD Students:

 

Anouk

Anouk van Oosten. Anouk was a BBSRC funded PhD student in the Silva Lab between 2009-2012. Her PhD degree was awarded in 2012. She has then moved back to the Netherlands to continue her career as a Clinical Research Associate. To see Anouk's publications click here.

Thorold Theunissen

Thorold Theunissen. Thor was a PhD student from the Wellcome Trust - Stem Cell PhD Programme between 2008-2011. His PhD degree was awarded in 2011. From 2012 he moved to the MIT to do a post-doc in the Professor Rudolf Jaenisch laboratory, Whitehead Institute, MIT, USA, being awarded a prestigious Sir Henry Wellcome Post-doctoral Fellowship. To see Thor's publications click here.

J. Silva Fig.4

Ornella Barrandon (2007-2011). PhD awarded in 2011. 2011-Post-doc in Prof. Douglas Melton laboratory, Harvard, USA

 

Plain English

Induced pluripotency is a recently discovered way of making cells equivalent to those present in the embryo and with the ability to form all the tissues in the body from adult cells. It involves introducing genes that are normally present in pluripotent cells into adult cells. The aim of our lab is to understand the biology of this process. We believe that this knowledge will bring us closer to using these cells in regenerative medicine and drug discovery.

Key Publications

  • Click here for Lab PUBMED and Google Scholar.
  • 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.
  • Radzisheuskaya A, Silva JCR. Do all roads lead to Oct4? The emerging concepts of induced pluripotency. Trends in Cell Biology. (2013) Dec 23. pii: S0962-8924(13)00223-7. doi: 10.1016/j.tcb.2013.11.010
  • 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.
  • 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.
  • 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. Oct 17, (2012) doi: 10.1242/​jcs.113019.
  • 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. May 8;3:827 (2012) doi: 10.1038/ncomms1822.
  • Theunissen TW, Costa Y, Radzisheuskaya 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.
  • 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.
  • Yang J, van Oosten AL, Theunissen TW, Guo G, Silva JCR, Smith A. Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell. (2010) Sep 3;7(3):319-28.
  • 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
  • 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.

(#) joint corresponding/senior authors

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From left to right: Rodrigo, Alex, José, Moyra, Hannah and Yael
Lab photo 2013

Lab photo 2013, Gonville & Caius College, Cambridge.

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