Abstract
A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes.
Highlights
In the healthy pancreas, the β-cell mass changes throughout life in response to insulin demand
We showed that Pdx1 expression facilitates tubular complex formation through acinar-to-ductal metaplasia induced by delivery of adenovirus vector expressing Isl1, a proendocrine transcription factor, into the exocrine pancreas of adult mice [35]
When Dox was removed from the drinking water from the time of conception, the ERTF-Pdx1-EGFP progeny mice showed severe dysmorphogenesis of the exocrine pancreas at 2 weeks of age (S1 Fig), quite similar to that observed in the mice expressing Pdx1 in the pancreas from the prenatal period [34]
Summary
The β-cell mass changes throughout life in response to insulin demand. It increases both through an increase in the volume of existing β cells and through their proliferation [1,2,3]. By tracing the lineage of genetically marked β cells in mice, Dor et al [4] showed that following birth or a 70% pancreatectomy, new β cells are mostly formed by self-replication. They can be generated by β-cell neogenesis. In animal models for β-cell regeneration, induced by partial pancreatectomy [5], cellophane wrapping [6], duct ligation [7], or PLOS ONE | DOI:10.1371/journal.pone.0161190 August 15, 2016
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