Characterization of a ciliogenic pancreatopathy reveals the essential role of centroacinar cells in pancratic homeostasis

Characterization of a ciliogenic pancreatopathy reveals the essential role of centroacinar cells in pancratic homeostasis Memoona Rajput Bhatti1, Angeline Fages1, Raphaël Helaers1, Axelle Loriot1, Younes Achouri1, Marine Fellmann1, Laurent Gatto1, Sophie Saunier2, Amandine Viau2, Alice Serafin2, Valentine Gillion3, Nathalie Godefroid4, Isabelle Scheers1,5§ & Patrick Jacquemin1§ 1: Institute de Duve, Université catholique de Louvain, Bruxelles, Belgique. 2: Institut Imagine, INSERM, Université Paris Cité, Paris, France. 3: Cliniques Universitaires Saint-Luc, Unité de Néphrologie, Bruxelles, Belgique. 4: Cliniques Universitaires Saint-Luc, Unité de Néphrologie Pédiatrique, Bruxelles, Belgique. 5: Cliniques Universitaires Saint-Luc, Unité de Gastroentérologie and Hépatologie Pédiatrique, Bruxelles, Belgique. § Co-senior auteurs. Introduction Ciliopathies are a group of genetic diseases causing cilia dysfunction. To date, a link between ciliopathies and pancreatic disease has not been established. In this context, we observed that certain patients followed for ciliopathies presented pancreatic abnormalities. We therefore sought to establish a link between ciliopathies and pancreatic disease. Methods We explored the presence of ciliary gene mutations in our cohort of patients and analyzed their pancreatic phenotype by imaging (MRI allowing quantification of the fat fraction). In parallel, we generated and analyzed two NPHP3 transgenic mouse models. The first model replicated the NPHP3 gene mutations present in a patient in our cohort (NPHP3mut1/mut2 model), the other allowed conditional inactivation of the NPHP3 gene in pancreatic ductal cells (NPHP3f/f model). Results We found mutations in the NPHP3 and HNF1 genes in some patients. Phenotypic analysis of both mouse models demonstrated that loss of function of NPHP3 in pancreatic ductal cells resulted in mild inflammation and fibrosis associated with significant acinar atrophy and severe lipomatosis. Further analysis revealed that ciliary dysfunction affects the function of centroacinar cells by disrupting the communications they establish with acinar cells and pancreatic fibroblasts. To investigate the possible presence of pancreatic lipomatosis in patients with NPHP3 and HNF1β mutations, we analyzed MRI on these patients and confirmed a significant increase in the percentage of fat in their pancreas compared to the pancreas of healthy controls. Conclusions These results highlight fundamental elements of pancreatic biology previously unknown, namely the existence of intercellular communications between different types of exocrine cells, and between exocrine cells and fibroblasts. They further reveal that disruption of ciliary function affects these communications and leads to a new form of pancreatic disease that we call ciliogenic pancreatopathy.