title: Pancreatic Inflammation Redirects Acinar to β Cell Reprogramming.
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 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.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Hannah W
authors.initials: HW
authors.lastname: Clayton
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Osipovich
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Stancill
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Judsen D
authors.initials: JD
authors.lastname: Schneider
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Vianna
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Shanks
authors.affiliation: Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Gu
authors.affiliation: Institute for Biomedical Informatics and Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Manduchi
authors.affiliation: Institute for Biomedical Informatics and Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Stoeckert
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: mark.magnuson@vanderbilt.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000473:pathology*; D000256:Adenoviridae / Q000378:metabolism; D000483:Alleles; D000818:Animals; D065150:Cellular Reprogramming / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D004318:Doxycycline / Q000494:pharmacology; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D007109:Immunity; D007249:Inflammation / Q000473:pathology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008679:Metaplasia; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000473:pathology*; D010183:Pancreatic Ducts / Q000473:pathology; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C064658:RAG-1 protein; D004318:Doxycycline
keywords: acinar cells; acinar-to-ductal metaplasia; beta cells; diabetes; inflammation; pancreas; reprogramming