Dr. Ludovic Vallier
Mechanisms Controlling Differentiation of Pluripotent Stem Cells into Definitive Endoderm
Anne McLaren Laboratory for Regenerative Medicine
Department of Surgery, University of Cambridge, Vallier Group Members
• Ms Stephanie Brown (Senior Research Assistant, MRC) • Dr Nicholas Hannan (Research Associate, EU LivES) • Dr Siim Pauklin (Research Associate) • Imbisaat Geti (Research Assistant, BRC hIPSCs core facility, NIHR) • Fiona Doherty (PhD student, BHF) • Charis-Patricia Segeritz (PhD student, CLDF) • Filipa Soares (PhD student, BHF) • Morteza Jalali (PhD student, CRUK) • Miguel Cardosa-de-Brito (PhD student, EU) • Alessandro Bertero (PhD student, BHF) • Mariya Chhatriwala (Senior Research Associate, WTSI) • Fotis Sampaziotis (Clinical Fellow, Addenbrooke's Charitable Trust) • Trey Gieseck (PhD student, NIH-Oxbridge) • Crystal Chia Ying (A STAR / Cambridge joint programme student) • Sapna Vyas (Research Assistant WTSI) • Pedro Madrigal • Kasia Tilgner • Rana Khairi
Ludovic graduated in Molecular biology and Immunology from the University Claude Bernard Lyon I in 1997. In 2001, he earned his PhD at Ecole Normale Superieur of Lyon in the group of Jacques Samarut, under the supervision of Pierre Savatier, studying mechanisms that control the cell cycle in mouse embryonic stem (ES) cells. Following a year in the biotechnology industry, Ludovic joined Professor Pedersen's group at the University of Cambridge Department of Surgery. In 2008 he joined the newly opened Anne McLaren Laboratory for Regenerative Medicine (LRM) as a Principal Investigator. Ludovic holds a joint appointment between the University of Cambridge and the Welcome Trust Sanger Institute where he is respectively Reader in Stem Cells and Regenerative Medicine and Senior Faculty. He is also the director of the Cambridge National Institute for Health Research (NIHR)/Biomedical Research Centre HiPSC (human induced pluripotent stem cell) core facility.
Tel: 01223 747489
Understanding the mechanisms controlling early cell fate specification in human development has major importance for regenerative medicine. Indeed the generation of fully functional cell types from stem cells may only be achievable by recapitulating a normal succession of cell fate decisions. The first event of differentiation of the embryo proper occurs at the stage of gastrulation with the specification of the three primary germ layers ectoderm, mesoderm and endoderm, from which all the cells of adult tissues are derived.
Endoderm(s) for Regenerative Medicine
The main objective of our group is to define the molecular mechanisms controlling the specification of the endoderm germ layer and also its subsequent differentiation into pancreatic and hepatic progenitors. For that, we use human puripotent stem cells (hESCs and hIPSCs) and mouse Epiblast Stem Cells (mEpiSCs) (Brons et al., Nature 2007) as in vitro model of development. The resulting knowledge allows the development of new culture system to drive differentiation of pluripotent stem cells into heptocytes and pancreatic Islet cells. Overall, our objective is not only to differentiate human pluripotent stem cells (hESCs/hIPSCs) into cell type relevant for clinical applications but also to acquire the knowledge necessary to differentiate any cell types into pancreatic and hepatic progenitors.
Molecular mechanisms controlling endoderm specification during mammalian development
The main focus of our laboratory consists in defining the network of transcription factors controlling the differentiation of pluripotent cells into endoderm from which key organs such as the pancreas and the liver are derived. We developed fully defined culture system to differentiate hESCs into neuroectoderm, mesendoderm, endoderm and extra-embryonic tissue (Vallier et al., Plos ONE 2009) (Figure 1). Using these culture systems, we are studying the function of key transcription factors involved in the transition between the pluripotent state and the endodermal state such as Nanog (Figure 2) (Vallier et al., Development 2009; Chng Z et al., Cell Stem Cell 2010; Teo et al., Genes and Dev 2011; Brown S. et al., Stem Cells 2011). We are also investing the molecular function of new regulators controlling early endoderm specification.
Fig. 1: Mechanisms Controlling Pluripotency in hESCs/hIPSCs and in mEpiSC
Generation of pancreatic progenitors useful for cell based therapy
Islets transplantation remains the most promising therapy to treat Type 1 diabetes but there is only enough donated islets to treat less than 1% of diabetic patients who might benefit from this form of treatment. Thus, the possibility of producing large numbers of pancreatic islets is a key challenge for transplantation based therapy (Docherty et al., Seminars in Cell and Developmental Biology 2007). A major objective of our group is to generate pancreatic progenitors from human pluripotent stem cells (hESCs/hIPSCs) using culture media compatibles with clinical applications (Figure 3). In addition, we are using these culture systems as in vitro model of development to study the molecular mechanisms controlling pancreatic specification during early mammalian development.
Fig. 2: Pancreatic cells generated from hESCs expressing C-peptide
In vitro modelling of metabolic diseases and cell based therapy for liver diseases
Generation of hepatocytes from human embryonic stem cells (hESCs) could represent an advantageous source for cell based therapy and also for drug and toxicity screening. Our group has developed a protocol to generate hepatoblasts form hESCs and hIPSCs using chemically defined medium (Touboul et al., Hepatology 2009, Rashid ST et al., JCI 2010, Yusa K et al., Nature 2011) (Figure 4). We are currently using this method to study the molecular mechanisms controlling hepatic specification during mammalian development. In addition, we are developing in vitro model to study metabolic diseases using hIPSCs derived from patients with liver metabolic diseases or Type 1 diabetes. Our laboratory has a strong expertise in hIPSCs especially regarding the mechanisms controlling their pluripotency and their differentiation (Vallier et al., Stem Cells 2009, Banito et al., Genes and Development 2009). Finally, our group has set up the hIPSCs core facility of the Laboratory For Regenerative Medicine (LRM) in the Cambridge MRC stem cells centre.
Fig. 3: Hepatocytes generated from hESCs expression Albumin and CK18
Plain EnglishThe objective of our research group is to acquire the basic knowledge and the clinical tools necessary to develop new therapies against metabolic diseases. For that, we use stem cells to produce liver and pancreatic cells with an interest for cell therapy of liver failure and diabetes.
- Brons IGM, Smithers LE., Trotter M., Rugg-Gunn P., Chuva de Sousa Lopes SM., Howlett SK., Clarkson A., Ahrlund-Richter L., Pedersen RA., Vallier L. (2007). Derivation of pluripotent Epiblast Stem Cells from pluripotent embryos. Nature. 12;448(7150):191-5.
- Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang – Doran I, Ahrlund- Richter L, Skepper J, Griffin J, Semple R, Weber A, Lomas DA, Vallier L. (2010) Modelling inherited metabolic disorders of the liver with human induced pluripotent stem cells. Journal of Clinical Investigations. J Clin Invest. 2010 Sep 1;120(9):3127-36.
- Chng ZZ, Teo A, Pedersen R*, Vallier L*(2010) SIP1 mediates cell fate decisions between neuroectoderm and mesendoderm in human embryonic pluripotent stem cells. Cell Stem Cell. 6(1). 59-70 * joint authorship.
- Teo AK, Arnold SJ, Trotter MWB, Brown S, Ang LT, Chng ZZ, Robertson EJ, Dunn NR* and Vallier L* (2011) Pluripotency Factors Regulate Definitive Endoderm Specification through Eomesodermin. Genes and Development. In press. * joint authorship.
- Yusa K*, Rashid ST*, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan N, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA*, Bradley A* and Vallier L* (2011). Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature. In press. *joint authorship.