Stellate cells are in utero markers of pancreatic disease in cystic fibrosis [scRNA-seq]
Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use the sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. Transcriptomic evidence from bulk RNA-seq showed alterations in the CF pancreas by 65 days of gestation, which are accompanied by marked pathological changes by 80 days gestation. These include a profound fibrotic response, confirmed by immunostaining for COL1A1, aSMA and SPARC, together with acinar destruction. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CF animals at 80- and 120-days gestation, as are activated stellate cells at term. This cellular imbalance likely has a pivotal role in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent CF pancreatic destruction. Overall design: Single cells from sheep (WT and CF) pancreas tissue  were isolated and analyzed using scRNA-seq.