image: Tooth epithelium (cell surface; yellow) and mesenchyme (cell surface; magenta). Proliferating cells (cyan) expand the tissue, generating a mechanical pressure at the tissue center that drives the formation of the main tooth signaling center or organizer, the enamel knot.
Credit: Neha Pincha Shroff & Pengfei Xu
Navigating the complex streets of some cities is certainly difficult without maps. We use all sorts of information, from maps on our cell phones to familiar stores and landmarks, to know where we are. Cells in our bodies face a similar problem when building our organs during embryogenesis. They need instructions on where to go and how to behave. Luckily, like cell phone towers in a city, embryos feature special cells in specific locations, known as organizers, that send signals to other cells and help them organize to build our complex organs.
Some of these signals are molecules sent from the organizer, a privileged signaling center. Cells around it receive stronger or weaker signals depending on their location, and they take decisions accordingly. Errors in the location of these messaging centers in the tissue lead to embryonic malformations that can be fatal. Scientists have known the relevance of these signaling centers for a long time, but how these appear at specific locations remained elusive.
It took an international collaboration of physicists and biologists to pinpoint the answer. Several years ago, the laboratories of Prof. Ophir Klein at Cedars-Sinai Guerin Children’s and the University of California, San Francisco (UCSF), and Prof. Otger Campàs at the Physics of Life Excellence Cluster of TU Dresden and the University of California, Santa Barbara (UCSB), had a hint of how it may work and joined forces. Together, they figured out that it is the mechanical pressure inside the growing tissue that dictates where the signaling center will emerge.
“Our work shows that both mechanical pressure and molecular signaling play a role in organ development,” said Ophir Klein, MD, PhD, Executive Director of Cedars-Sinai Guerin Children’s, where he is also the David and Meredith Kaplan Distinguished Chair in Children’s Health, and co-corresponding author of the study.
The study, published today in Nature Cell Biology, shows that as cells grow in the embryonic incisor tooth, they feel the growing pressure and use this information to organize themselves. “It’s like those toys that absorb water and grow in size,” said Neha Pincha Shroff, PhD, a postdoctoral scholar in the School of Dentistry at UCSF, and co-first author of the study. “Just imagine that happening in a confined space. What happens in the incisor knot is that the cells multiply in number in a fixed space and this causes a pressure to build up at the center, which then becomes a cluster of specialized cells.” Like people in a crowded bar, cells in the tissue start feeling the squeeze from their peers. The researchers found that the cells feeling the stronger pressure stop growing and start sending signals to organize the other surrounding cells in the tooth. They were literally pressed into becoming the tooth organizer.
“We were able to use microdroplet techniques that our lab previously developed to figure out how the buildup of mechanical pressure affects organ formation,” said co-corresponding author of the study Otger Campàs, PhD, who is currently Managing Director, Professor and Chair of Tissue Dynamics at the Physics of Life Excellence Cluster of TU Dresden, and former Associate Professor of Mechanical Engineering at UCSB. “It is really exciting that tissue pressure has a role in establishing signaling centers. It will be interesting to see if or how mechanical pressure affects other important developmental processes.”
Embryos use several of these signaling centers to guide cells as they form tissues and organs. Like building skyscrapers or bridges, sculpting our organs involves tight planning, a lot of coordination and the right structural mechanics. Failure in any of these processes can be catastrophic when it comes to building a bridge, and it can also be damaging for us when growing in the womb.
“By understanding how an embryo forms organs, we can start to ask questions about what goes wrong in children born with congenital malformations,” said Ophir Klein. “This work may lead to additional research into how birth defects are formed and can be prevented.”
Investigators: Pengfei Xu (co-first author), Sangwoo Kim, Elijah Shelton, Ben Gross, Yucen Liu, Carlos Gomez, Qianlin Ye, Tingsheng Yu Drennon, Jimmy Hu, and Jeremy Green also participated in the study.
Funding: The study was funded by the National Institute of Dental and Craniofacial Research (OK and OC) in the USA, the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy, and the Cluster of Excellence Physics of Life of TU Dresden (OC).
Study: Neha Pincha Shroff, Pengfei Xu, Sangwoo Kim, Elijah R. Shelton, Ben J. Gross, Yucen Liu, Carlos O. Gomez, Qianlin Ye, Tingsheng Yu Drennon, Jimmy K. Hu, Jeremy B. A. Green, Otger Campàs, Ophir D. Klein (2024): Proliferation-driven mechanical compression induces signalling centre formation during mammalian organ development. DOI: 10.1038/s41556-024-01380-4.
About the Cluster of Excellence Physics of Life
Physics of Life (PoL) is one of three clusters of excellence at TU Dresden. It focuses on identifying the physical laws underlying the organization of life in molecules, cells, and tissues. In the cluster, scientists from physics, biology, and computer science investigate how active matter in cells and tissues organizes itself into given structures and gives rise to life. PoL is funded by the DFG within the framework of the Excellence Strategy. It is a cooperation between scientists of the TU Dresden and research institutions of the DRESDEN-concept network, such as the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG), the Max Planck Institute for the Physics of Complex Systems (MPI-PKS), the Leibniz Institute of Polymer Research (IPF) and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR). www.physics-of-life.tu-dresden.de
About TU Dresden
TUD Dresden University of Technology, as a University of Excellence, is one of the leading and most dynamic research institutions in Germany. With around 8,300 members of staff and around 29,000 students in 17 Faculties, it is one of Europe’s largest technically-oriented universities. Founded in 1828, today it is a globally oriented, regionally anchored top university, developing innovative solutions for the world's most pressing issues. In research and academic programs, the university unites the natural and engineering sciences with the humanities, social sciences and medicine. This wide range of disciplines is an outstanding feature that facilitates interdisciplinarity and transfer of science to society.
Journal
Nature Cell Biology
Article Title
Proliferation-driven mechanical compression induces signalling centre formation during mammalian organ development