Mimicking Mother Nature to Grow an Artificial Gland

Our salivary glands secrete up to a quart of saliva every day—enough to fill a large milk carton. We need this saliva to chew and digest food, ward off harmful microbes, and protect our teeth and oral tissues. People who lose salivary gland function—due to certain diseases or radiation therapy for head and neck cancer—can have problems tasting and swallowing food and are at higher risk for tooth decay and oral infections.

To help such patients, NIDCR scientists are exploring several ways to restore salivary function, including working toward making artificial salivary glands to replace damaged ones. Now, researchers in the lab of Ken Yamada, MD, PhD, and colleagues at the National Institute of Biomedical Imaging and Bioengineering, report that they have achieved a key first step in growing a replacement gland. The work was led by Shaohe Wang, PhD, a research fellow in Yamada’s lab and recipient of an NIDCR research grant designed to support postdoctoral researchers as they transition to independent scientists. The team’s findings appeared June 15 in the journal Cell.

The scientists started by documenting how salivary glands naturally develop in mouse embryos. “It’s a process we feel is important to understand in detail in order to mimic nature’s approaches to efficiently create artificial organs,” says Yamada, an NIH distinguished investigator who heads NIDCR’s Cell Biology Section.

Using a technique called two-photon microscopy, the researchers were able to track the movements of embryonic salivary gland cells in real time. They noticed that certain cells were more prone than others to adhering to their neighbors. These “stickier” cells tended to bunch together at the core of the structure, while the less sticky cells moved freely to the outer edges and adhered to the basement membrane, the sheet-like matrix of proteins encasing the gland. The actions of the cells pushing at the edges caused the outer layer of the gland to expand faster than the core and to buckle inward, splitting existing protrusions, or “buds,” into new buds. This process, called budding, occurs many times to drive a gland’s growth into a mature organ that contains thousands of saliva-secreting, globe-like structures.

Using what they’d learned about cell behavior in the embryonic mouse gland, the team set out to recreate the process in cells grown in a dish. “We engineered the cells to tune down their stickiness to each other, and we provided a basement membrane for the cells to grab onto,” says Wang. With that, “we observed robust budding in this synthetic system.”

“It’s exciting that we can now create the first key step in salivary gland development—the budding of tissues,” says Yamada. He notes, however, that much work remains before they can grow an artificial gland from start to finish. Because other organs, such as the pancreas, undergo budding during development, Yamada says, “at least some of the principles we learned here could also be used for engineering other organs.”

Reference

Budding epithelial morphogenesis driven by cell-matrix versus cell-cell adhesion. Wang S, Matsumoto K, Lish SR, Cartagena-Rivera AX, Yamada KM. Cell. 2021 Jun 9;S0092-8674(21)00632-2. doi: 10.1016/j.cell.2021.05.015. Online ahead of print. PMID: 34133940

NIH Support: In addition to NIDCR, support for this research came from the National Institute of Biomedical Imaging and Bioengineering.

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