title: Macrophage/epithelium cross-talk regulates cell cycle progression and migration in pancreatic progenitors.
abstract: Macrophages populate the mesenchymal compartment of all organs during embryogenesis and have been shown to support tissue organogenesis and regeneration by regulating remodeling of the extracellular microenvironment. Whether this mesenchymal component can also dictate select developmental decisions in epithelia is unknown. Here, using the embryonic pancreatic epithelium as model system, we show that macrophages drive the epithelium to execute two developmentally important choices, i.e. the exit from cell cycle and the acquisition of a migratory phenotype. We demonstrate that these developmental decisions are effectively imparted by macrophages activated toward an M2 fetal-like functional state, and involve modulation of the adhesion receptor NCAM and an uncommon "paired-less" isoform of the transcription factor PAX6 in the epithelium. Over-expression of this PAX6 variant in pancreatic epithelia controls both cell motility and cell cycle progression in a gene-dosage dependent fashion. Importantly, induction of these phenotypes in embryonic pancreatic transplants by M2 macrophages in vivo is associated with an increased frequency of endocrine-committed cells emerging from ductal progenitor pools. These results identify M2 macrophages as key effectors capable of coordinating epithelial cell cycle withdrawal and cell migration, two events critical to pancreatic progenitors' delamination and progression toward their differentiated fates.
authors.affiliation: Department of Medicine, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kristin
authors.initials: K
authors.lastname: Mussar
authors.affiliation: Department of Medicine, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tucker
authors.affiliation: Department of Medicine, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Linsey
authors.initials: L
authors.lastname: McLennan
authors.affiliation: Department of Medicine, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Addie
authors.initials: A
authors.lastname: Gearhart
authors.affiliation: Department of Medicine, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Jimenez-Caliani
authors.affiliation: Department of Medicine, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cirulli
authors.affiliation: Department of Medicine, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Crisa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001837:Body Weights and Measures; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004848:Epithelium / Q000502:physiology*; D005434:Flow Cytometry; D006652:Histological Techniques; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000196:embryology*; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D019006:Neural Cell Adhesion Molecules