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  • Final Activity Report Summary - INTESTINAL STEM CELL (Characterization of the mechanisms controlling Intestinal Stem Cell specification and positioning. Use of Intestinal Stem Cells)

Final Activity Report Summary - INTESTINAL STEM CELL (Characterization of the mechanisms controlling Intestinal Stem Cell specification and positioning. Use of Intestinal Stem Cells)

The intestinal epithelium is a prime example of cell renewal in adult tissues. The proliferative compartment of the intestinal epithelium is structured in millions of 'bag-shaped' invaginations, known as crypts of Lieberkuhn. Each of these structures is a developmental unit that contributes to the complete renewal of the epithelium every few days during the entire adulthood. Cell renewal in the intestinal epithelium is maintained by a small group of intestinal stem cells, estimated between one and six, which reside at the bottom of each crypt. These stem cells duplicate slowly but continuously, giving rise to a transient population of progenitor cells that rapidly divide whilst migrating towards the intestinal lumen. During their migration, precursor progenitors become determined towards the functional lineages present in the intestine. Cell cycle arrest and differentiation proceed once these cells reach the surface epithelium.

The study of intestinal stem cells and their potential therapeutic use was hampered by the absence of specific markers that identified them, as well as by the lack of intestinal stem cell cultures. The project entitled 'Characterisation of the mechanism controlling intestinal stem cell specification and positioning. Use of intestinal stem cells in tissue regeneration', was part of the ongoing research by Eduard Batlle. It aimed to develop methods of intestinal stem cells' isolation and to study the potential of these adult stem cells to regenerate adult tissues.

This Marie Curie grant was instrumental in developing a method for crypt progenitor cells' purification. This method allowed us to separate and purify stem and progenitor cells from a complex mixture of disaggregated intestinal epithelial cells from mice. The developed methodology was anticipated to be the base for the purification of intestinal stem cells in regenerative medicine.

Eph receptors belonged to the largest family of receptor tyrosine kinases. Compelling evidence indicated that interaction of Eph receptors with their ephrin ligands resulted in cell-to-cell repulsion. We recently described that, in the intestinal epithelium, EphB3 receptor positioned paneth cells at the bottom of the crypts while the graded expression of EphB2 appeared to control the unidirectional migration of the intestinal precursors along the crypt axis. The expression of EphB receptors and ephrinB ligands was inversely controlled by beta-catenin or Tcf activity along the intestinal crypt axis and in colorectal cancer initiation. Furthermore, we recently demonstrated that EphB activity suppressed colorectal cancer progression and, consequently, EphB expression was down-regulated in the majority of advanced human colorectal carcinomas despite constitutive Wnt signalling.

This proposal also aimed to understand the mechanism of cell positioning trigger by EphB signalling in intestinal cells. The Marie Curie grant allowed us to develop an in vitro cell culture model that mimicked EphB-mediated compartmentalisation. The analysis of this model allowed us to dissect the different steps that were necessary for the process of cell sorting. In addition, we identified several downstream components of EphB signalling. This in vitro model was evaluated as being instrumental to further understand how EphB receptors positioned epithelial cells and suppressed colorectal cancer.

Reported by

Josep Samitier, 1-5
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