title: Reprogramming of human pancreatic exocrine cells to β-like cells.
abstract: Rodent acinar cells exhibit a remarkable plasticity as they can transdifferentiate to duct-, hepatocyte- and islet β-like cells. We evaluated whether exocrine cells from adult human pancreas can similarly respond to proendocrine stimuli. Exocrine cells from adult human pancreas were transduced directly with lentiviruses expressing activated MAPK (mitogen-activated protein kinase) and STAT3 (signal transducer and activator of transcription 3) and cultured as monolayers or as 3D structures. Expression of STAT3 and MAPK in human exocrine cells activated expression of the proendocrine factor neurogenin 3 in 50% to 80% of transduced exocrine cells. However, the number of insulin-positive cells increased only in the exocrine cells grown initially in suspension before 3D culture. Lineage tracing identified human acinar cells as the source of Ngn3- and insulin-expressing cells. Long-term engraftment into immunocompromised mice increased the efficiency of reprogramming to insulin-positive cells. Our data demonstrate that exocrine cells from human pancreas can be reprogrammed to transplantable insulin-producing cells that acquire functionality. Given the large number of exocrine cells in a donor pancreas, this approach presents a novel strategy to expand cell therapy in type 1 diabetes.
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Lemper
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Leuckx
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Heremans
authors.affiliation: Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143-0669, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: German
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Heimberg
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Bouwens
authors.affiliation: 1] Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium [2] Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143-0669, USA.
authors.forename: L
authors.initials: L
authors.lastname: Baeyens
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D054338:Cell Transdifferentiation / Q000235:genetics*; D017690:Cell Transplantation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000637:transplantation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009419:Nerve Tissue Proteins; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C498695:NEUROG3 protein, human; C494086:STAT3 protein, human