Abstract
The exocrine pancreas can give rise to endocrine insulin-producing cells upon ectopic expression of key transcription factors. However, the need for genetic manipulation remains a translational hurdle for diabetes therapy. Here we report the conversion of adult human nonendocrine pancreatic tissue into endocrine cell types by exposure to bone morphogenetic protein 7. The use of this U.S. Food and Drug Administration-approved agent, without any genetic manipulation, results in the neogenesis of clusters that exhibit high insulin content and glucose responsiveness both in vitro and in vivo. In vitro lineage tracing confirmed that BMP-7-induced insulin-expressing cells arise mainly from extrainsular PDX-1(+), carbonic anhydrase II(-) (mature ductal), elastase 3a (acinar)(-) , and insulin(-) subpopulations. The nongenetic conversion of human pancreatic exocrine cells to endocrine cells is novel and represents a safer and simpler alternative to genetic reprogramming.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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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Biomarkers / metabolism
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Bone Morphogenetic Protein 7 / genetics
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Bone Morphogenetic Protein 7 / metabolism
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Bone Morphogenetic Protein 7 / pharmacology*
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C-Peptide / blood
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C-Peptide / metabolism
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Cell Lineage
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Cell Transdifferentiation / drug effects*
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Cells, Cultured
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Diabetes Mellitus, Experimental / blood
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Experimental / therapy*
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Fluorescent Antibody Technique
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Homeodomain Proteins / metabolism
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Humans
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / drug effects*
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / pathology
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Insulin-Secreting Cells / transplantation
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Kidney
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Male
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Mice, Nude
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Pancreas, Exocrine / drug effects*
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Pancreas, Exocrine / metabolism
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Pancreas, Exocrine / pathology
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Trans-Activators / metabolism
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Transplantation, Heterologous
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Transplantation, Heterotopic
Substances
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BMP7 protein, human
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Biomarkers
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Bone Morphogenetic Protein 7
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C-Peptide
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Homeodomain Proteins
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Insulin
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Recombinant Proteins
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein