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Cell Rep ; 17(8): 2028-2041, 2016 11 15.
Article in English | MEDLINE | ID: mdl-27851966

ABSTRACT

Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to ß-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new ß-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new ß-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.


Subject(s)
Acinar Cells/pathology , Cellular Reprogramming , Inflammation/pathology , Insulin-Secreting Cells/pathology , Pancreas/pathology , Acinar Cells/drug effects , Adenoviridae/metabolism , Alleles , Animals , Cellular Reprogramming/drug effects , Diabetes Mellitus, Experimental/pathology , Doxycycline/pharmacology , Gene Expression Profiling , Homeodomain Proteins/metabolism , Immunity , Insulin-Secreting Cells/drug effects , Macrophages/drug effects , Macrophages/pathology , Metaplasia , Mice, Transgenic , Organ Size/drug effects , Pancreatic Ducts/pathology , Reproducibility of Results , Transcription Factors/metabolism , Transgenes
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