Promise of regenerating tissues and organs from inside the body

Regenerative medicine holds tremendous promise for many ailments, from curing diabetes with pancreatic cell transplants to growing new organs for transplant. But because these approaches generate tissue ex vivo, or outside the body, scientists developing them all face the same conundrum: How can they connect these externally developed tissues to the bloodstream and the rest of the body so they can thrive?

Scientists in Wendell Lim’s lab at UC San Francisco hope that a synthetic signaling molecule, dubbed synNotch, will allow scientists to create tissues and organs within the body, with ready-made connections. They used synNotch to program groups of cells to differentiate into different types of structures, mimicking how cells naturally “talk” to each other and decide how to organize themselves into tissues, according to a statement. Specifically, they programmed cells to respond to signals coming from adjacent cells by making “sticky” molecules called cadherins and fluorescent marker proteins.

They made a series of increasingly more complicated structures, starting with a two-layered sphere. A group of colorless cells expressing synNotch were programmed to detect a signal protein expressed by a second group of blue cells. When combined, the blue cells activated the clear cells’ synNotch, prompting them to produce the velcro-like cadherins and a green marker protein. This caused the colorless cells to clump together and turn green, forming the core of the sphere, surrounded by an outer layer of blue cells.

While the structures the team built were relatively simple, “these minimal intercellular programs were sufficient to yield assemblies with hallmarks of natural developmental systems: robust self-organization into multidomain structures, well-choreographed sequential assembly, cell type divergence, symmetry breaking and the capacity for regeneration upon injury,” they wrote in their study, which appears in Science. Lim thinks that combining multiple layers of synNotch signaling will pave the way for the generation of “ever more complex” tissues.

“People talk about 3D-printing organs, but that is really quite different from how biology builds tissues. Imagine if you had to build a human by meticulously placing every cell just where it needs to be and gluing it in place,” said Lim, a Howard Hughes Medical Institute investigator and member of the UCSF Helen Diller Family Comprehensive Cancer Center, in the statement. “It’s equally hard to imagine how you would print a complete organ, then make sure it was hooked up properly to the bloodstream and the rest of the body. The beauty of self-organizing systems is that they are autonomous and compactly encoded. You put in one or a few cells, and they grow and organize, taking care of the microscopic details themselves.”

In a similar tack, researchers in the U.S. and Japan developed a new cell culture method to combat a problem with pancreatic islets—the tendency to lose their blood vessels when they are being prepared for transplant. The method, called self-condensation cell culture, allowed the scientists to grow new pancreatic islets complete with endothelial cells, which improved post-transplant engraftment.

SynNotch was first developed in Lim’s lab by co-authors Kole Roybal and Leonardo Morsut. At the time, they used it to tweak T cells, improving their ability to recognize cancer cells and destroy them. The technology has the potential to make engineered T-cell treatments more specific and therefore applicable in solid tumors. It could also be used to suppress the immune response, which could be useful in treating autoimmune disease, the scientists said at the time.

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