New small molecule helps scientists study regeneration

Treating intestinal organoids with a newly discovered molecule results in an inc
Treating intestinal organoids with a newly discovered molecule results in an increase in cell proliferation. Image credits: Clara Baader/FMI

Regenerating damaged tissues or organs has been a dream of scientists for decades. Now, researchers at the FMI and Novartis Biomedical Research have discovered a new molecule that activates a protein involved in regeneration. The tool holds promise for advancing our understanding of how organisms repair damaged tissue.

During embryo development and throughout life, specific molecules act as signals that orchestrate cell growth and organ size. One of these molecules - a protein called YAP - not only tells cells to grow and multiply, it is also involved in healing wounds and repairing damaged tissues.

Given YAP’s potential for promoting tissue regeneration, scientists at Novartis Biomedical Research sought to manipulate the protein’s activity. To do so, they screened many synthetic small molecules and identified one, which they called NIBR-LTSi, that activated YAP.

To investigate how NIBR-LTSi affects tissue regeneration, the researchers teamed up with Clara Baader, a PhD candidate in the Liberali group at the FMI. The Liberali group has significant expertise in establishing and using 3D models of the mouse gut, known as mouse intestinal organoids. These intestinal organoids accurately mimic the structure and function of the gut epithelium, a tissue that helps the body absorb nutrients from food and preserve the intestinal barrier.

Treating the intestinal organoids with NIBR-LTSi activated YAP and resulted in an increase in cell proliferation. The findings hint that activating YAP may boost tissue regeneration.

However, as the organoids’ regenerative potential increased, the number of mature, functional intestinal cells decreased, the researchers found. In the long run, this side effect may compromise the structure and function of the tissue, Baader cautions.

"The expertise of our lab has been instrumental in understanding the adverse effects, particularly on the intestine, observed with systemic YAP activation," she says.

Although more work is needed before small molecules like NIBR-LTSi can find applications in the clinic, the tool promises to advance our understanding of tissue regeneration by allowing scientists to target YAP in multiple experimental settings.

Treating mice with NIBR-LTSi results in an increase in proliferating cells (red) in the intestine. Cell nuclei are shown in blue. Image credits: Namoto, Baader, Orsini, et al. Cell Stem Cell

Original publication:

Kenji Namoto*, Clara Baader*, Vanessa Orsini*, Alexandro Landshammer, Eva Breuer, Kieu Trinh Dinh, Rosemarie Ungricht, Monika Pikiolek, Stephane Laurent, Bo Lu, Alexandra Aebi, Katharina Schönberger, Eric Vangrevelinghe, Olivera Evrova, Tianliang Sun, Stefano Annunziato, Julie Lachal, Emily Redmond, Louis Wang, Kristie Wetzel, Paola Capodieci, Jonathan Turner, Gabi Schutzius, Vincent Unterreiner, Markus Trunzer, Nicole Buschmann, Dirk Behnke, Rainer Machauer, Clemens Scheufler, Christian N. Parker, Magali Ferro, Armelle Grevot, Armin Beyerbach, Wei-Yu Lu, Stuart J. Forbes, Jürgen Wagner, Tewis Bouwmeester, Jun Liu, Bindi Sohal, Sukhdeep Sahambi, Linda E. Greenbaum, Felix Lohmann, Philipp Hoppe, Feng Cong, Andreas W. Sailer, Heinz Ruffner, Ralf Glatthar, Bostjan Humar, Pierre-Alain Clavien, Michael T. Dill, Elizabeth George, Jürgen Maibaum, Prisca Liberali, Jan S. Tchorz NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo Cell Stem Cell (2024) Advance online publication
*co-first authors

About the FMI first author

Clara Baader studied Molecular Biology at the University of Heidelberg in Germany. In 2019, she joined Prisca Liberali’s lab for her PhD. Clara’s research focuses on the mechano-chemical feedback during stem cell niche formation in mouse small intestinal organoids. Clara is passionate about art and enjoys outdoor activities in her free time.