Abstract
Neurogenin 3 (NGN3) is necessary and sufficient for endocrine differentiation during pancreatic development and is expressed by a population of progenitor cells that give rise exclusively to hormone-secreting cells within islets. NGN3 protein can be detected in the adult rodent pancreas only following certain types of injury, when it is transiently expressed by exocrine cells undergoing reprogramming to an endocrine cell fate. Here, NGN3 protein can be detected in 2% of acinar and duct cells in living biopsies of histologically normal adult human pancreata and 10% in cadaveric biopsies of organ donor pancreata. The percentage and total number of NGN3+ cells increase during culture without evidence of proliferation or selective cell death. Isolation of highly purified and viable NGN3+ cell populations can be achieved based on coexpression of the cell surface glycoprotein CD133. Transcriptome and targeted expression analyses of isolated CD133+ / NGN3+ cells indicate that they are distinct from surrounding exocrine tissue with respect to expression phenotype and Notch signaling activity, but retain high level mRNA expression of genes indicative of acinar and duct cell function. NGN3+ cells have an mRNA expression profile that resembles that of mouse early endocrine progenitor cells. During in vitro differentiation, NGN3+ cells express genes in a pattern characteristic of endocrine development and result in cells that resemble beta cells on the basis of coexpression of insulin C-peptide, chromogranin A and pancreatic and duodenal homeobox 1. NGN3 expression in the adult human exocrine pancreas marks a dedifferentiating cell population with the capacity to take on an endocrine cell fate. These cells represent a potential source for the treatment of diabetes either through ex vivo manipulation, or in vivo by targeting mechanisms controlling their population size and endocrine cell fate commitment.
Highlights
Endocrine hormones secreted by pancreatic islets maintain glucose homeostasis throughout life
Neurogenin 3 (NGN3) protein was localized in the nucleus of cytokeratin 19 (CK19)+ duct cells and amylase (AMY)+ acinar cells
No expression of NGN3 could be detected within insulin C-peptide (CPEP)+ or chromogranin A (CHGA)+ islets
Summary
Endocrine hormones secreted by pancreatic islets maintain glucose homeostasis throughout life. Beta cell neogenesis has been demonstrated from exocrine cells that transiently express NGN3 following adenoviral expression [35], partial duct ligation [27, 28], 90% pancreatectomy [37, 38], in vivo delivery of EGF and CNTF [39] or LIF [40], in vivo knockdown of E3 ligase Fbw7 [41], expression of STAT3 and MAPK [42] and in vivo expression of PDX1, MAFA and NGN3 [43] These results do not demonstrate exocrine to endocrine reprogramming or transdifferentiation under normal in vivo circumstances, they establish that exocrine cells have the capacity to take on an endocrine cell fate and strongly suggest a role for NGN3 in this process
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