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In the past, scientists believed that the fast-acting biochemistry of genes and proteins was responsible for directing the forces that shape developing organs. But a new study from Syracuse University shows that steady, powerful flows of tissue might be equally significant in shaping an organ's development as biochemistry. By understanding this physical process, doctors could find ways to prevent or treat human illness.

"We've shown that mechanical interactions are just as important as those biochemical signaling interactions in organ development," says M. Lisa Manning, the William R. Kenan, Jr. Professor of Â鶹ÒùÔºics in the College of Arts and Sciences (A&S) as well as founding director of the BioInspired Institute at Syracuse University.

"The two work together. This is a new and emerging idea coming out of a lot of different labs across the country—that mechanics working together with the biochemistry that does robust patterning of organs."

She co-authored the , recently published in Proceedings of the National Academy of Sciences, with Raj Kumar Manna, a former postdoctoral researcher in the Department of Â鶹ÒùÔºics at A&S; Heidi Hehnly, associate professor of biology at A&S; Jeffrey Amack, professor of cell and developmental biology at the State University of New York Upstate Medical University; Emma Retzlaff, a graduate student at Upstate Medical University; and members of the Amack and Hehnly labs across the BioInspired Institute.

Organs move, driving shape change

Syracuse researchers are looking for answers in a tiny, fluid-filled, balloon-shaped structure called Kupffer's vesicle (KV) in zebrafish embryos. KV, a temporary organ of about 100 cells, shapes the zebrafish's body symmetry. KV tells the fish on which side of the body its organs must develop.

During its brief existence, KV is slowly pushed and pulled by self-generated cellular forces through the surrounding tissue in the zebrafish's tailbud toward its tail. This movement of KV builds pressure in the surrounding tissue, which also starts to migrate, slowly but steadily and powerfully.

Most scientists previously thought that moving tissues do not play a significant role in shaping organs. But slow-moving tissues generate mechanical forces that can mold organs as they develop, the new study found.

"There is a gradient of stiffness in the tissues around Kupffer's vesicle, with a less-stiff tissue that flows like honey on the side closer to the head, and a stiffer solid-like tissue closer to the tail," says Manning. "When you have this balloon-like organ moving through thick honey-like tissue and nearly solid tissue, it creates strong forces in the tissues. And even these very slow tissue movements can drive forces that are surprisingly large."

With mathematical models, live imaging and physical experiments, the researchers tested how slow-tissue motion affects KV's shape.

The models showed that slow-moving tissues generate enough physical force to help sculpt KV. Then, using precise laser tools, the team disrupted those forces in living embryos. The organ's shape changed in exactly the way their models predicted.

Powerful potential

These findings could help researchers understand how parts of the body form, not just in fish but also in humans, informing regenerative medicine and treatments for birth defects in organs and other conditions.

"I am working with scientists who will extend these research ideas to human organoids, which are useful for things like tissue transplants," says Manning. "We are also studying how these dynamical forces affect cancer tumors."