title: Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters.
abstract: Regeneration of insulin-producing β-cells from resident pancreas progenitors requires an understanding of both progenitor identity and lineage plasticity. One model suggested that a rare β-cell sub-population within islets demonstrated multi-lineage plasticity. We hypothesized that β-cells from young mice (postnatal day 7, P7) exhibit such plasticity and used a model of islet dedifferentiation toward a ductal epithelial-cell phenotype to test this theory. RIPCre;Z/AP(+/+) mice were used to lineage trace the fate of β-cells during dedifferentiation culture by a human placental alkaline phosphatase (HPAP) reporter. There was a significant loss of HPAP-expressing β-cells in culture, but remaining HPAP(+) cells lost insulin expression while gaining expression of the epithelial duct cell marker cytokeratin-19 (Ck19). Flow cytometry and recovery of β-cell subpopulations from whole pancreas vs. islets suggest that the HPAP(+)Ck19(+) cells had derived from insulin-positive, glucose-transporter-2-low (Ins(+)Glut2(LO)) cells, representing 3.5% of all insulin-expressing cells. The majority of these cells were found outside of islets within clusters of <5 β-cells. These insulin(+)Glut2(LO) cells demonstrated a greater proliferation rate in vivo and in vitro as compared to insulin(+)Glut2(+) cells at P7, were retained into adulthood, and a subset differentiated into endocrine, ductal, and neural lineages, illustrating substantial plasticity. Results were confirmed using RIPCre;ROSA- eYFP mice. Quantitative PCR data indicated these cells possess an immature β-cell phenotype. These Ins(+)Glut2(LO) cells may represent a resident population of cells capable of forming new, functional β-cells, and which may be potentially exploited for regenerative therapies in the future.
authors.affiliation: a Department of Physiology and Pharmacology , Western University , London , ON , Canada.|d Children's Health Research Institute , London , ON , Canada.|e Lawson Health Research Institute, St Joseph Health Care , London , ON , Canada.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Beamish
authors.affiliation: b Department of Medicine , Western University , London , ON , Canada.|e Lawson Health Research Institute, St Joseph Health Care , London , ON , Canada.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Strutt
authors.affiliation: b Department of Medicine , Western University , London , ON , Canada.|c Department of Pathology , Western University , London , ON , Canada.|d Children's Health Research Institute , London , ON , Canada.|e Lawson Health Research Institute, St Joseph Health Care , London , ON , Canada.
authors.forename: Edith J
authors.initials: EJ
authors.lastname: Arany
authors.affiliation: a Department of Physiology and Pharmacology , Western University , London , ON , Canada.|b Department of Medicine , Western University , London , ON , Canada.|d Children's Health Research Institute , London , ON , Canada.|e Lawson Health Research Institute, St Joseph Health Care , London , ON , Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hill
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000502:physiology; D000066670:Cell Plasticity; D005434:Flow Cytometry; D051246:Glucose Transport Proteins, Facilitative / Q000032:analysis*; D007328:Insulin / Q000032:analysis*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D053539:Keratin-19 / Q000032:analysis; D051379:Mice; D008856:Microscopy, Fluorescence
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D053539:Keratin-19
keywords: Glut2; differentiation; duct; islet; pancreas; plasticity; progenitor cell; β-cell