An international collaboration led by IBEC and supported by the Fundació "la Caixa" measures cell forces in mini-intestines for the first time in the lab

Discovering how the wall of the intestine folds and moves by measuring its forces

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The human intestine is made up of more than 40 square metres of tissue, with a multitude of folds on its inner surface reminiscent of valleys and mountain peaks, to achieve, among other objectives, increased absorption of nutrients. It has the particularity of being in constant renewal, which means that approximately every five days all the cells of its internal wall are renewed to guarantee the correct functioning of the intestine.

Until now it was known that this renewal was possible thanks to stem cells that are protected in the so-called crypts or intestinal valleys, which give rise to new differentiated cells. However, the process that leads to the concave shape of the crypts and the migration of the new cells to the intestinal summits was hitherto unknown.

Now, an international team led by Xavier Trepat, ICREA Research Professor at the Institute for Bioengineering of Catalonia (IBEC) and CaixaResearch researcher, in collaboration with IRB, researchers at the UB and UPC universities in Barcelona, and the Institut Curie in Paris, has deciphered the mechanism by which crypts adopt and maintain their concave shape, and how the movement of cell migration towards the summits occurs, without the intestine losing its characteristic folded shape.

The work, published in the prestigious journal Nature Cell Biology, has combined computer modelling, led by UPC professor Marino Arroyo, IBEC associate researcher and CIMNE member, with experiments with intestinal organoids from mouse cells, and shows that this process is possible thanks to the mechanical forces exerted by the cells.

An important part of this study has been supported by the "la Caixa" Foundation within the framework of the CaixaResearch programme. The organisation has also awarded a grant to the first co-author, Gerardo Ceada, to do his PhD at IBEC.

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Forces determine and control the shape of the intestine and the movement of cells

Using mouse stem cells and bioengineering and mechanobiology techniques, the researchers have developed mini-intestines, organoids that reproduce the three-dimensional structure of valleys and peaks recapitulating the functions of the tissue in vivo. Using microscopy technologies developed in the same group, they have performed, for the first time, high-resolution experiments that have made it possible to obtain 3D maps showing the forces exerted by each cell.

Moreover, with this in vitro model, the researchers have shown that the movement of the new cells towards the top is also controlled by mechanical forces exerted by the cells themselves, specifically by the cytoskeleton, a network of filaments that determines and maintains cell shape.

"With this system, we have discovered that the crypt is concave because the cells have more tension on their upper surface than on their lower surface, which causes them to adopt a conical shape. When this happens in several cells next to each other, the result is that the tissue folds, giving rise to a relief of valleys and peaks," says Carlos Pérez-González, co-first author of the paper.

"Contrary to what was believed until now, we have been able to determine that it is not the cells in the intestinal crypt that push the new cells upwards, but the cells at the top that pull the new ones upwards, something like a climber who helps another climber to climb by pulling him up," Gerardo Ceada, co-first author of the paper.

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The new mini-intestine model will allow the study, under reproducible and real conditions, of diseases such as cancer, coeliac disease or colitis, in which there is a lack of control in the multiplication of stem cells or a destructuring of the folds. In addition, gut organoids can be made from human cells and used for the development of new drugs or the study of the intestinal microbiota.

X. Trepat is a member of the Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN).

Reference article:

C. Pérez-González, G. Ceada, F. Greco, M. Matejčić, M. Gómez-González, N. Castro, A. Menendez, S. Kale, D. Krndija, A. G. Clark, V. Ram Gannavarapu, A. Álvarez-Varela, P. Roca-Cusachs, E. Batlle, D. Matic Vignjevic, M. Arroyo and X. Trepat. Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration. Nature Cell Biology, 2021.

About IBEC

The Institute for Bioengineering of Catalonia (IBEC) is a CERCA centre, twice recognised as a Severo Ochoa Centre of Excellence, and a TECNIO-labelled technology developer and business enabler. IBEC is a member of the Barcelona Institute of Science and Technology (BIST) and carries out multidisciplinary research excellence at the frontier between engineering and life sciences to generate knowledge, integrating fields such as nanomedicine, biophysics, biotechnology, tissue engineering and applications of information technologies in the field of health. IBEC was created in 2005 by the Generalitat de Catalunya, the Universitat de Barcelona (UB) and the Universitat Politècnica de Catalunya (UPC).

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