Gallus gallus

For the higher eukaryotic organisms, self-renewal is both a vital necessity and a mortal danger. The vital necessity is related to the constant requirement for regeneration of tissues (for example, the human body produces 200 billion red blood cells every day). The greatest danger resides in the appearance of uncontrolled self-renewal, resulting in a cancer which can destroy the organism.

Our understanding of the molecular mechanisms involved in this essential process is still very limited. In the laboratory we have elaborated a strategy for the analysis of this biological phenomenon which is based on the following hypotheses:

1. This process is not under the control of a single gene, but of a group of genes which function as a network which we call a “self-renewal module”.
2. This process should be conserved between different types of stem cells, from pluripotent embryonic cells to monopotent adult cells. It seems probable that this conservation will not be on a gene-to-gene basis, but that it will be the modules, or functions involved that will be conserved.
3. This process is conserved during evolution, also on a modular scale. Inter-species comparisons should therefore prove very instructive.

The importance of this project is above all fundamental: the comprehension of the mechanisms which control self-renewal is a major challenge in contemporary biology.
This project is likely to have medical implications in two different directions: first, the ability to control the process of self-renewal may make it possible to maintain large quantities of human somatic stem cells in culture, and to amplify them in large quantities for use in cell therapy. Secondly, the understanding of dysfunctions responsible for tumoral phenomena may lead to research strategies for cancer therapy by forced differentiation. Finally, the economic importance is mainly for the chicken, which is a species of major agronomic importance (world chicken production reached 51 million tons in 2001). Recent advances have been made by characterizing groups of genes for which expression appears to be specific to stem cells. These high throughput approaches have led to the establishment of catalogues of genes for “stemness”, (in the sense of "characteristics of stem cells"; Ivanova et al., 2002; Ramalho-Santos et al., 2002). The way in which the products of these genes interact to produce the self-renewal phenotype nevertheless remains to be completely characterized.

This objective of this project is to extract a self-renewal module. To extract this type of module, a transcriptomic approach based on the utilization of the SAGE method has been selected. This method possesses huge advantages; for instance, it is quantitative, exhaustive and easy to implement rapidly for the whole organism.
This technique has been applied to two complementary cellular models, according to our initial hypotheses:

1. Monopotent avian stem cells (T2ECs)
2. Transformed human neural stem cells

Inter-cell conservation should permit extraction of this type of module by inter-species comparisons (human-chicken in this case) and between developmental stages (embryonic stem cells versus somatic cells in this case).