Group leader: 

David Hay

Position: 

RCUK Fellow

Contact: 

davehay [at] talktalk [dot] net

Aims
To develop viable and high fidelity hepatocytes from human pluripotent stem cells for use in vitro drug testing, disease modeling and bio-artificial construction.

Background
I have established a laboratory within the Centre in which we are defining novel ways to derive hepatocytes from pluripotent stem cells. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), unlike their adult stem cell counterparts, can be propagated indefinitely when cultured in conditions that suppress their differentiation. These unique attributes allow large numbers of cells to be differentiated to particular cell lineages and promises an almost unlimited supply of specific cell types. With reference to human development, we have generated robust and physiological differentiation models allowing us to study human liver development and hepatocyte function in vitro.  Employing the approaches stated below, we have developed a model system which has important roles to play in the generation of predictive in vitro models and human extra-corporal devices.



Hepatocyte-like cells derived from human embryonic stem cells, expressing E-Cadherin.

Collaborations
We work collaboratively with a number of groups in Edinburgh: John Iredale, Stuart Forbes, James Ross, Rowan Parks, Josh Brickman, Steve Wigmore, Ian Wilmut, Paul Desousa and Mark Bradley. Additionally, we collaborate with Ron Hay and the University of Dundee; David Adams and Phil Newsome, University of Birmingham; Lorraine Young, University of Nottingham; Dr Petter Björquist, Cellartis; Dr Aidan Courtney, Roslin Cells and Dr Chuck Ohler, Primorigen Corp, USA.

Approaches and progress
Development - Cross referencing development with in vitro models
Drug Metabolism - Predictive model development
Disease Modeling - Predictive model development
Model System Definition - With a view to GMP manufacture
Translation - Extra-corporeal device construction

Selected publications

• Zhou W, Hannoun Z, Jaffray E, Medine CN, Black JR, Greenhough S, Ross JA, Forbes SJ, Wilmut I, Iredale JP, Hay RT, Hay DC. 2012. SUMOylation of HNF4α Regulates Protein Stability and Hepatocyte Function. Journal of Cell Science. In press.
• 
• Hay DC, Pernagallo S, Diaz-Mochon JJ, Medine CN, Greenhough S, Hannoun Z, Schrader J, Black JR, Fletcher J, Dalgetty D, Thompson AI,  Newsome PN, Forbes SJ, Ross JA, Bradley M, Iredale JP. 2011.  Unbiased Screening of Polymer Libraries to Define Novel Substrates for Functional Hepatocytes with Inducible Drug Metabolism. Stem Cell Research 6:92-102.  www.sciencedirect.com/science/journal/18735061
• Payne CM, Samuel K, Pryde A, King J, Brownstein D, Schrader J, Medine CN, Forbes SJ, Iredale JP, Newsome PN, Hay DC. 2011. Persistence of Functional Hepatocyte Like Cells in Immune Compromised Mice. Liver International 31(2):254-62. http://onlinelibrary.wiley.com/doi/10.1111/liv.2010.31.issue-2/issuetoc
• Hannoun Z, Fletcher J, Greenhough S, Medine CN, Samuel K, Sharma R , Pryde A, Black JR, Ross JA, Wilmut I, Iredale JP, Hay DC. 2010. The Comparison between Conditioned Media and Serum Free Media in Human Embryonic Stem Cell Culture and Differentiation. Cellular Reprogramming 12 (2): 133-140. www.liebertonline.com/doi/abs/10.1089/cell.2009.0099.
• Sullivan GJ, Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, Dalgetty D, Black JR, Ross JA, Samuel K, Wang G, Daley GQ, Lee JH, Church GM, Forbes SJ, Iredale JP, Wilmut I. 2010. Generation of Functional Human Hepatic Endoderm from Human iPS cells. Hepatology 51(1):329-35. www3.interscience.wiley.com/journal/122612538/abstract. Press release.
• Hay DC, Fletcher J, Payne C, Terrace JD, Gallagher RCJ, Snoeys J, Black J, Wojtacha D, Samuel K, Hannoun Z, Pryde A, Filippi C, Currie IS, Forbes SJ, Ross JA, Newsome P, Iredale JP. 2008. Highly Efficient Differentiation of hESCs to Functional Hepatic Endoderm Requires ActivinA and Wnt3a Signalling. Proceedings of the National Academy of Sciences 105(34):12301-6. www.pnas.org/content/105/34/12301

Funding
Research Councils UK
Technology Strategy Board
Medical Research Council
Scottish Stem Cell Network
Chief Scientist Office