Pancreatic Inflammation Redirects Acinar to β Cell Reprogramming

• Published in: Cell reports (Cambridge) 2016-11, Vol.17 (8), p.2028-2041
• Main Authors: Clayton, Hannah W., Osipovich, Anna B., Stancill, Jennifer S., Schneider, Judsen D., Vianna, Pedro G., Shanks, Carolyn M., Yuan, Weiping, Gu, Guoqiang, Manduchi, Elisabetta, Stoeckert, Christian J., Magnuson, Mark A.
• Format: Article
• Language: English
• Subjects: acinar cells; Acinar Cells - drug effects; Acinar Cells - pathology; acinar-to-ductal metaplasia; Adenoviridae - metabolism; Alleles; Animals; beta cells; Cellular Reprogramming - drug effects; diabetes; Diabetes Mellitus, Experimental - pathology; Doxycycline - pharmacology; Gene Expression Profiling; Homeodomain Proteins - metabolism; Immunity; inflammation; Inflammation - pathology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - pathology; Macrophages - drug effects; Macrophages - pathology; Metaplasia; Mice, Transgenic; Organ Size - drug effects; pancreas; Pancreas - pathology; Pancreatic Ducts - pathology; Reproducibility of Results; reprogramming; Transcription Factors - metabolism; Transgenes
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.10.068

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 β-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 β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new β-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. [Display omitted] •Inflammation redirects the outcome of transcription factor-mediated reprogramming•Reprogramming factor concentration affects the outcome of acinar cell reprogramming•Overly robust reprogramming factor expression causes acinar cell damage and death Clayton et al. show that the outcome of acinar to β cell reprogramming depends on both the concentration of the reprogramming factors and inflammation. Overly robust expression of reprogramming factors causes acinar cell damage and death, a potent inflammatory response, and acinar-to-ductal cell metaplasia, thereby preventing acinar to β cell reprogramming.