Transdifferentiation of pancreatic ductal cells to endocrine β-cells

Abstract

The regenerative process in the pancreas is of particular interest, since diabetes, whether Type 1 or Type 2, results from an inadequate amount of insulin-producing beta-cells. Islet neogenesis, or the formation of new islets, seen as budding of hormone-positive cells from the ductal epithelium, has long been considered to be one of the mechanisms of normal islet growth after birth and in regeneration, and suggested the presence of pancreatic stem cells. Results from the rat regeneration model of partial pancreatectomy led us to hypothesize that differentiated pancreatic ductal cells were the pancreatic progenitors after birth, and that with replication they regressed to a less differentiated phenotype and then could differentiate to form new acini and islets. There are numerous supportive results for this hypothesis of neogenesis, including the ability of purified primary human ducts to form insulin-positive cells budding from ducts. However, to rigorously test this hypothesis, we took a direct approach of genetically marking ductal cells using CAII (carbonic anhydrase II) as a duct-cell-specific promoter to drive Cre recombinase in lineage-tracing experiments using the Cre-Lox system. We show that CAII-expressing pancreatic cells act as progenitors that give rise to both new islets and acini after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes either in vivo or ex vivo.

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue

“…Other reports have indicated that CK19-expressing cells, believed to be of ductal origin, are the in vitro and in vivo precursors of b-cells (Gao et al 2003, Hao et al 2006. Lineage tracing studies of pancreatic ductal cells revealed that they are the in vivo progenitor, producing new islets after injury (Bonner-Weir et al 2008). However, Solar et al (2009) reported no such contribution of pancreatic ductal epithelium in postnatal endocrine or acinar cell development.…”

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

“…This mechanism essentially represents acceleration of an otherwise slow-paced self-replicating process that occurs under normal conditions (36)(37)(38). In contrast, acute insults such as pancreatectomy or ductal ligation provoke neogenesis as opposed to self-replication as the major mechanism of b-cell regeneration (7,(39)(40)(41). In these studies, neogenesis was induced due to major physical or genetic manipulations of the tissue in order to detect b-cell regeneration (pancreatectomy, ductal ligation, and genetic manipulation) (7,(29)(30)(31)(32)(33).…”

Attributes of adult stem cells

“…Direct lineage tracing, in which Cre recombinase was driven by a duct cell-specific promoter (carbonic anhydrase II), has shown that after pancreatic duct ligation (PDL), a population of less differentiated ductal cells emerges that expresses Pdx1 and contributes to islets [113]. PDL also causes up-regulation of the embryonic pancreas transcription factor Ngn3 in the ductal cells, and direct lineage tracing has also found that these cells can become insulin-positive cells [114].…”