Ttc7 in lymphocytes and fibroblasts is a critical regulator of epithelial proliferation in the mouse

Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue Ttc7 result in a multisystemic disease, mostly affecting epithelial barriers and immune defence. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening. Consequently, there is an ongoing debate of whether TTC7A mutations dysregulate epithelial cells only, or whether a cell-intrinsic defect in lymphocytes contributes to disease manifestations. Here, we have shown that severity of epithelial hyperproliferation was accentuated by lymphocytes in a Ttc7-mutated mouse model, whereas the phenotype was not induced by the transfer of Ttc7-mutated hematopoietic cells. Mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. In a xenograft model, Ttc7-mutated mouse fibroblasts induced markedly increased epithelial proliferation of human keratinocytes. Thus, Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. Our results reveal a previously unsuspected, fundamental role of Ttc7 in the communication between cells and stress the need of molecular targeted treatment strategies to tune collective cell behaviour.