title: Contribution of a non-β-cell source to β-cell mass during pregnancy.
abstract: β-cell mass in the pancreas increases significantly during pregnancy as an adaptation to maternal insulin resistance. Lineage tracing studies in rodents have presented conflicting evidence on the role of cell duplication in the formation of new β-cells during gestation, while recent human data suggest that new islets are a major contributor to increased β-cell mass in pregnancy. Here, we aim to: 1) determine whether a non-β-cell source contributes to the appearance of new β-cells during pregnancy and 2) investigate whether recapitulation of the embryonic developmental pathway involving high expression of neurogenin 3 (Ngn3) plays a role in the up-regulation of β-cell mass during pregnancy. Using a mouse β-cell lineage-tracing model, which labels insulin-producing β-cells with red fluorescent protein (RFP), we found that the percentage of labeled β-cells dropped from 97% prior to pregnancy to 87% at mid-pregnancy. This suggests contribution of a non-β-cell source to the increase in total β-cell numbers during pregnancy. In addition, we observed a population of hormone-negative, Ngn3-positive cells in islets of both non-pregnant and pregnant mice, and this population dropped from 12% of all islets cells in the non-pregnant mice to 5% by day 8 of pregnancy. Concomitantly, a decrease in expression of Ngn3 and changes in its upstream regulatory network (Sox9 and Hes-1) as well as downstream targets (NeuroD, Nkx2.2, Rfx6 and IA1) were also observed during pregnancy. Our results show that duplication of pre-existing β-cells is not the sole source of new β-cells during pregnancy and that Ngn3 may be involved in this process.
authors.affiliation: Department of Pediatrics, Alberta Children's Hospital Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Chiara
authors.initials: C
authors.lastname: Toselli
authors.affiliation: Department of Pediatrics, Alberta Children's Hospital Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Hyslop
authors.affiliation: Department of Pediatrics, Alberta Children's Hospital Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Martha
authors.initials: M
authors.lastname: Hughes
authors.affiliation: Department of Reproductive Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Natale
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Institut D'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.affiliation: Department of Pediatrics, Alberta Children's Hospital Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Carol T L
authors.initials: CT
authors.lastname: Huang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000502:physiology*; D058948:Cell Tracking; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins; D011247:Pregnancy; D000071701:Regulatory Factor X Transcription Factors; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins; D000097573:Red Fluorescent Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D055758:SOX9 Transcription Factor; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000097573:Red Fluorescent Protein; C489734:Hes1 protein, mouse; C000715631:NKX2-2 protein, human; C407737:Neurog3 protein, mouse; C000715627:Nkx2-2 protein, mouse; C547963:Rfx6 protein, mouse; C527933:Sox9 protein, mouse; C000715630:nkx2.2b protein, zebrafish; C093564:Neurogenic differentiation factor 1