Dr José Silva

Biology of Induced Pluripotency

Laboratory Location:

Wellcome Trust Centre for Stem Cell Research, Silva Lab Members

Departmental Affiliation:

Principal investigator of Wellcome Trust Centre for Stem Cell Research, Department of Biochemistry, University of Cambridge. Associate Principal Investigator of EuroSyStem.

Co-workers:

• Yael Costa • Moyra Lawrence • Aliaksandra Radzisheuskaya • Rodrigo Santos • Anouk van Oosten

Learn more about Dr José Silva

Education

José received his first degree in Biology from the University of Porto, in Portugal. He entered 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 discoveries in the field of induced pluripotency which is his current area of research.

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

Description
More information

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

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.

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.

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).

Past Lab Members

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PhD Students:

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

Thorold Theunissen (2008-2011). 2012-Post-doc in Professor Rudolf Jaenisch
laboratory, Whitehead Institute, MIT, 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

View all publications by
Dr José Silva

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) 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, Silva JCR^#. Switching on pluripotency: a perspective on the biological requirement of Nanog. Philos Trans R Soc Lond B Biol Sci. (2011) Aug 12;366(1575):2222-9.
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.
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.
Silva J, Chambers I, Pollard S, Smith A. Nanog promotes transfer of pluripotency after cell fusion. Nature. (2006) Jun 22;441(7096):997-1001. Epub 2006 Jun 14.

(^#) corresponding author(s)

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Lab photo Christmas 2010. From left to right: Jose, Thor, Ornella, Alex, Ana and Yael Silva Lab 2011. From left to right: Moyra, Rodrigo, Yael, Thor, Jose, Anouk and Alex