Use of a dual genetic system to decipher exocrine cell fate conversions in the adult pancreas

Abstract

Unraveling cell fate plasticity during tissue homeostasis and repair can reveal actionable insights for stem cell biology and regenerative medicine. In the pancreas, it remains controversial whether lineage transdifferentiation among the exocrine cells occur under pathophysiological conditions. Here, to address this question, we used a dual recombinase-mediated genetic system that enables simultaneous tracing of pancreatic acinar and ductal cells using two distinct genetic reporters, avoiding the “ectopic” labeling by Cre-loxP recombination system. We found that acinar-to-ductal transdifferentiation occurs after pancreatic duct ligation or during caerulein-induced pancreatitis, but not during homeostasis or after partial pancreatectomy. On the other hand, pancreatic ductal cells contribute to new acinar cells after significant acinar cell loss. By genetic tracing of cell proliferation, we also quantify the cell proliferation dynamics and deduce the turnover rate of pancreatic exocrine lineages during homeostasis. Together, these results suggest that the lineage transdifferentiation happens between acinar cells and ductal cells in the pancreatic exocrine glands under specific conditions.

Targeting ductal-endothelial crosstalk alleviate pancreatitis

“…In the emergence of acute pancreatitis, there is a pivotal cellular event in which the pancreatic acinar cells differentiate to CK19 + ductal-like cells, a cellular process known as acinar-to-ductal metaplasia (ADM)(2, 24, 25). Given that ADM is a hallmark feature of acute pancreatitis, we examined the spatial distribution of CK19 + cells to identify potential cell types that might interact with them.…”

Perfect duet: Dual recombinases improve genetic resolution

“…In the research of cell fate conversion among exocrine cells, previous studies have been contradictory about the contribution of ductal cells to acinar cells in adults, 28–30 as is the case with acinar‐to‐ductal metaplasia 31,32 . Based on a sequential recombination system, Tnni3‐Dre;CK19‐CreER;IR1 mice were generated to label ductal cells and acinar cells with different fluorescent proteins 33 . Given that CK19 is expressed in the majority of ductal cells and few acinar cells, constitutive Dre‐mediated Dre‐ rox recombination preferentially and specifically occurs in Tnni3 + acinar cells, preventing the ‘ectopic’ labelling by CK19‐CreER in acinar cells.…”

“…31,32 Based on a sequential recombination system, Tnni3-Dre; CK19-CreER;IR1 mice were generated to label ductal cells and acinar cells with different fluorescent proteins. 33 Given that CK19 is expressed in the majority of ductal cells and few acinar cells, constitutive Dre-mediated Dre-rox recombination preferentially and specifically occurs in Tnni3 + acinar cells, preventing the 'ectopic' labelling by CK19-CreER in acinar cells. In this way, the two types of cells can be labelled with distinct genetic markers simultaneously (Figure 1E, F).…”

Changes in Pancreatic Senescence Mediate Pancreatic Diseases

“…The vast majority of the pancreas is exocrine pancreas, and about 95% of the exocrine pancreas consists of acinar cells and duct cells [ 2 , 3 ]. The pancreatic acinar cells produce and release many digestive enzymes, including amylases, lipases, and proteinases, while the ductal cells transport these enzymes into the duodenum [ 4 ]. Li et al also found that adult pancreatic acinar cells might be an important source of β-cell neogenesis [ 5 ].…”