Centroacinar Cells Are Progenitors That Contribute to Endocrine Pancreas Regeneration

Abstract

Diabetes is associated with a paucity of insulin-producing β-cells. With the goal of finding therapeutic routes to treat diabetes, we aim to find molecular and cellular mechanisms involved in β-cell neogenesis and regeneration. To facilitate discovery of such mechanisms, we use a vertebrate organism where pancreatic cells readily regenerate. The larval zebrafish pancreas contains Notch-responsive progenitors that during development give rise to adult ductal, endocrine, and centroacinar cells (CACs). Adult CACs are also Notch responsive and are morphologically similar to their larval predecessors. To test our hypothesis that adult CACs are also progenitors, we took two complementary approaches: 1) We established the transcriptome for adult CACs. Using gene ontology, transgenic lines, and in situ hybridization, we found that the CAC transcriptome is enriched for progenitor markers. 2) Using lineage tracing, we demonstrated that CACs do form new endocrine cells after β-cell ablation or partial pancreatectomy. We concluded that CACs and their larval predecessors are the same cell type and represent an opportune model to study both β-cell neogenesis and β-cell regeneration. Furthermore, we show that in cftr loss-of-function mutants, there is a deficiency of larval CACs, providing a possible explanation for pancreatic complications associated with cystic fibrosis.

Centroacinar cells: At the center of pancreas regeneration

“…However, the regenerative response of the mammalian pancreas can vary depending on the injury model (Criscimanna et al, 2011; Kopp et al, 2011; Lee et al, 2006; Li et al, 2010; Nagasao et al, 2005; Xu et al, 2008), making uncovering mechanisms of regeneration in those animals difficult. On the other hand, as we will discuss here, the zebrafish pancreas displays a remarkable capacity for regeneration (Delaspre et al, 2015; Ghaye et al, 2015; Moss et al, 2009). A detailed understanding of how the fish pancreas regenerates is thus the critical first step towards achieving endogenous β-cell replacement therapy in humans.…”

“…In both zebrafish and mammals, transmission electron microscopy studies of CAC ultrastructure have detailed a unique ruffled nuclear morphology and the close association of CACs with both acinar and other ductal cells via tight junctions (Parsons et al, 2009; Pour, 1994) (Figure 3E). Interestingly, contrasting other duct cells that contribute to cuboidal and columnar epithelium, in all vertebrates examined CACs have long cytoplasmic extensions (Figure 1C and 2D) that extend along the duct to contact neighboring CACs and into the parenchyma to touch other neighboring cells, including islets (Delaspre et al, 2015; Leeson and Leeson, 1986; Pour, 1994). Notably, zebrafish CACs seem to have much longer extensions than mammalian CACs.…”

“…Bicarbonate secretion serves to neutralize acid entering the duodenum from the stomach and avoid the aggregation of digestive enzymes in the pancreatic lumen. CACs in fish and mammals also express several aquaporins and calcium ion channels such as Cftr and Clcn1 (Burghardt et al, 2003; Delaspre et al, 2015; Marino et al, 1991; Trezise and Buchwald, 1991). Thus, CACs play an important role in maintaining the ionic content of the ductal lumen and keep it open for fluid flow.…”

“…In the zebrafish, a population of pancreatic Notch-responsive cells have been well recognized for their progenitor capacity during development (Dalgin and Prince, 2015; Delaspre et al, 2015; Delous et al, 2012; Huang et al, 2014; Manfroid et al, 2012; Ninov et al, 2012; Parsons et al, 2009; Rovira et al, 2011; Wang et al, 2015; Wang et al, 2011). Recently, these cells have been revealed to be specialized ductal cells called centroacinar cells (CACs) (Delaspre et al, 2015), which also serve as progenitors to regenerate β cells in the adult zebrafish (Delaspre et al, 2015; Ghaye et al, 2015).…”

“…Recently, these cells have been revealed to be specialized ductal cells called centroacinar cells (CACs) (Delaspre et al, 2015), which also serve as progenitors to regenerate β cells in the adult zebrafish (Delaspre et al, 2015; Ghaye et al, 2015). CACs are a cell type common to all vertebrates and have several defining characteristics: they are a ductal cell type positioned at the center of acini, with unique cell morphology, active Notch signaling, and expression of the endocrine differentiation regulator Sox9 (Kopp et al, 2011; Manfroid et al, 2012; Seymour, 2014; Seymour et al, 2008; Shih et al, 2012).…”