The biology of human tuft cells – PhD defense Lulu Huang

Several of our organs, including our lungs and intestines, are lined with mucosal tissue that creates a boundary between our bodies and the external environment. This tissue is composed of epithelial cells that play an important role in respiration, nutrient absorption and pathogen defense. To execute these different functions, the epithelial cells work together with immune cells and neuronal cells, that it is strongly interweaved with.

Tuft cell organoids

Tuft cells are rare chemosensory epithelial cells that have brush-like microvilli projecting from the cells. They are found in the multiple organs, where they detect pathogens and allergens and subsequently interact with the immune and nervous systems to coordinate protective responses. But since their discovery, it has become clear that they also sense and respond to damaged intestinal tissue. Lulu created organoid models of human tuft cells to better study their anatomy and function.

Reserve stem cells

To her surprise, she found that a single human tuft cell from the gut was able to grow into a functional organoid that contained the main types of epithelial cells normally found in the gut lining. Unlike in mice, human tuft cells could proliferate and contribute to regeneration of the gut epithelium. This means that tuft cells can act as reserve stem cells in the human intestine. “The moment I received the email that my paper about this finding was accepted was a major highlight of my PhD,” Lulu says. “I actually had a similar dream just a few days before.”

Regeneration signals

To target tuft cells to enhance regeneration of the gut lining, they engineered a protein that could boost the signals that tell tuft cells to multiply and repair tissue. These regenerative properties make the tuft cell interesting as a therapeutic target for wound repair in the intestines where normal stem cell function is affected (e.g. because of disease or chemotherapy). However, it remains a challenge to specifically target the regeneration of tuft cells, because the signals that lead to their expansion are common and broadly active in various tissues. Manipulating these signals therefore poses potential risks due to their broad effects on other cells.

Different organ, different function

Lulu also investigated tuft cells in the lungs. She found that, unlike intestinal tuft cells, they do not appear to proliferate. Instead, they work with nearby immune cells to rapidly detect bacteria and trigger a targeted defense. When she exposed human airway organoids to bacteria, they produced a signal called IL-23, which activated immune cells to boost mucus production and antimicrobial defenses, helping protect the lungs.

To future PhD students, Lulu advises to establish an efficient workflow early on, though she also admits that it can be frustrating when experiments fail repeatedly. “Ultimately, it taught me how to be critical in my troubleshooting. Most things are unexpected but exciting,” Lulu adds.