title: Suppression of Ptf1a activity induces acinar-to-endocrine conversion.
abstract: Pluripotent embryonic cells become progressively lineage restricted during development in a process that culminates in the differentiation of stable organ-specific cell types that perform specialized functions. Terminally differentiated pancreatic acinar cells do not have the innate capacity to contribute to the endocrine β cell lineage, which is destroyed in individuals with autoimmune diabetes. Some cell types can be reprogrammed using a single factor, whereas other cell types require continuous activity of transcriptional regulators to repress alternate cell fates. Thus, we hypothesized that a transcriptional network continuously maintains the pancreatic acinar cell fate. We found that postembryonic antagonism of Ptf1a, a master regulator of pancreatic development and acinar cell fate specification, induced the expression of endocrine genes including insulin in the exocrine compartment. Using a genetic lineage tracing approach, we show that the induced insulin+ cells are derived from acinar cells. Cellular reprogramming occurred under homeostatic conditions, suggesting that the pancreatic microenvironment is sufficient to promote endocrine differentiation. Thus, severe experimental manipulations may not be required to potentiate pancreatic transdifferentiation. These data indicate that targeted postembryonic disruption of the acinar cell fate can restore the developmental plasticity that is lost during development.
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics, and Human Genetics, Institute for Regeneration Medicine, Liver Center, and Diabetes Center, University of California, San Francisco, 1550 Fourth Street, San Francisco, CA 94158, USA. daniel_hesselson@hotmail.com
authors.forename: Daniel
authors.initials: D
authors.lastname: Hesselson
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Anderson
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000196:embryology* / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000196:embryology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D029961:Zebrafish Proteins; C062602:transcription factor PTF1