Pressured to become the organizer

A collaboration between the Campàs group at PoL, the University of California, and Cedars-Sinai Guerin Children’s in Los Angeles, has identified how organizers orchestrate the formation of teeth.

The image depicts a colourful arrangement of cell types, including tooth epithelium marked in yellow, and mesenchymal cells marked in magenta, both on the cell surface. Additionally, proliferating cells marked in cyan are found throughout the 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. © Neha Pincha Shroff & Pengfei Xu

Building tissues and organs during embryonic development involves a remarkable cellular choreography. Orchestrating cells in this process requires special organizers, but it is unclear how these are set in the embryo. A collaboration between research groups at the Physics of Life Excellence Cluster of TU Dresden in Germany, the University of California, and Cedars-Sinai Guerin Children’s in Los Angeles, have now identified how these special organizers are located in the tissue to orchestrate the formation of teeth.

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).