Dr. Ludovic Vallier

Mechanisms Controlling Differentiation of Pluripotent Stem Cells into Definitive Endoderm

Email: lv225@cam.ac.uk

Laboratory Location:

Anne McLaren Laboratory for Regenerative Medicine

Departmental Affiliation:

Department of Surgery, University of Cambridge, Vallier Group Members

Co-workers:

• Ms Stephanie Brown (Senior Research Assistant, MRC) • Dr Nicholas Hannan (Research Associate, EU LivES) • Dr Siim Pauklin (FEBS fellow) • Dr Mina Brimpari (Research Associate, TSB) • Dr Sheik Tamir Rashid (Wellcome Trust Clinical researcher) • Candy Cho (PhD student, MRC) • Imbisaat Geti (Research Assistant, BRC hIPSCs core facility, NIHR) • Fiona Doherty (PhD student, BHF) • Foad Rouhani (Clinical PhD student, Sanger Institute) • Charis-Patricia Segeritz (PhD student, CLDF) • Neil Singh (Clinical researcher)

Lab Information 

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 mEpiSCs

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. 4: 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