The Biology of human tuft cells

In this thesis, I investigated the biology of human tuft cells, a rare epithelial cell type present across multiple endoderm-derived mucosal tissues. Although tuft cells have emerged over the past decade, most current knowledge of tuft cells originates from murine studies, in which tuft cells have been described as post-mitotic chemosensory cells that primarily function in type 2 immune circuits. While these studies have provided critical insights, the biology of tuft cells in human tissues has remained incompletely understood due to the scarcity of tuft cells in primary human samples. Using human adult stem cell-derived organoids, we identified that human intestinal tuft cells can act as a damage-resistant reserve stem cell pool. Unlike their post-mitotic murine counterparts, in response to type 2 cytokines (IL-4/IL-13), human intestinal tuft cells can proliferate and generate all major epithelial lineages to drive tissue repair following irradiation. In parallel, we found that airway tuft cells function as active coordinators of immune plasticity: they constitutively express IL-23 to maintain homeostatic ILC3 populations and can reprogram immune responses during bacterial infections. In addition, we present a translational application by engineering a synthetic Wnt–IL-13 fusion protein. This dual-pathway activator potently stimulates intestinal tuft cell-mediated regeneration, offering a novel therapeutic paradigm aimed at enhancing epithelial restoration in diseases such as inflammatory bowel disease and graft-versus-host disease.