Abstract
Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin(+) β-cells, glucagon(+) α-cells, and somatostatin(+) δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and β-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. DOI: http://dx.doi.org/10.7554/eLife.01846.001.
Keywords:
acinar to endocrine conversion; direct lineage conversion; in vivo reprogramming; islet delta, alpha, beta cells; pancreatic endocrine cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Lineage
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Cell Transdifferentiation
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Cellular Reprogramming*
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Gene Expression Regulation, Developmental
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Genes, Reporter
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Glucagon-Secreting Cells / metabolism
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Glucagon-Secreting Cells / physiology*
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HEK293 Cells
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / physiology*
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Luminescent Proteins / biosynthesis
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Luminescent Proteins / genetics
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Maf Transcription Factors, Large / genetics
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Maf Transcription Factors, Large / metabolism
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Mice, Knockout
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Pancreas, Exocrine / cytology
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Pancreas, Exocrine / metabolism
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Pancreas, Exocrine / physiology*
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Red Fluorescent Protein
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Somatostatin-Secreting Cells / metabolism
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Somatostatin-Secreting Cells / physiology*
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Time Factors
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transfection
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Homeodomain Proteins
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Luminescent Proteins
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Maf Transcription Factors, Large
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Nerve Tissue Proteins
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein
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RAG-1 protein