Gene network-based maturation of embryonic stem cell-derived hepatocytes in a microfabricated array

Objective

Embryonic stem cells (ESC) have a limitless capacity for self-renewal a remarkable ability to differentiate, promising a limitless source of cells for cell therapies and tissue engineering. Organ scarcity and lack of proliferative ability makes ESC-derived hepatocytes one of the few potential sources of cells for clinical applications and pharmaceutical drug discovery. However, current techniques for hepatocyte differentiation result in mixed cell populations, minimal metabolic function, and long-term de-differentiation. These differences between mature and differentiated hepatocytes are due to insufficient development of the hepatic transcriptional network during differentiation. Preliminary evidence suggests that modifying the nutritional state of ESC-derived hepatocytes by lowering glucose and increasing fatty acids, mimicking suckling, results in a more mature hepatic phenotype, possibly through the induction of the fatty acid-responsive nuclear receptors, PPARa and HNF4a. This result is interesting as the role of nutrients in differentiation has yet to be elucidated in spite of well known nutritional changes during the pre- and post-natal periods. The hepatic nuclear receptor network is especially important in this context as these ligand-activated transcription factors respond to glucose, sterols, fatty and bile acids offering an epigenetic point of regulation in the development of liver metabolism. The technology which allows us to elucidate and control transcriptional events during differentiation is a microdevice termed the Living Cell Array (LCA). The LCA is a microfabricated device containing multiple GFP reporter cells under microfluidic control allowing high-throughput screening of changes in transcriptional activity during ESC differentiation. The ability of the LCA to monitor transcriptional activity dynamics in high-throughput makes it a unique tool for the study of hepatocyte differentiation under varying nutritional stimulation.

Fields of science (EuroSciVoc)

CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.

• medical and health sciences basic medicine pharmacology and pharmacy drug discovery
• medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs
• medical and health sciences medical biotechnology tissue engineering
• medical and health sciences medical biotechnology cells technologies stem cells
• medical and health sciences clinical medicine obstetrics postnatal care

Programme(s)

Multi-annual funding programmes that define the EU’s priorities for research and innovation.

• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Topic(s)

Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.

• FP7-PEOPLE-2009-RG - Marie Curie Action: "Reintegration Grants"

Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

FP7-PEOPLE-2009-RG
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Funding Scheme

Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.

MC-IRG - International Re-integration Grants (IRG)

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