Contribution of a non-β-cell source to β-cell mass during pregnancy

• Published in: PloS one 2014-06, Vol.9 (6), p.e100398-e100398
• Main Authors: Toselli, Chiara, Hyslop, Colin M, Hughes, Martha, Natale, David R, Santamaria, Pere, Huang, Carol T L
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biology and Life Sciences; Cell cycle; Cell Differentiation; Cell growth; Cell lineage; Cell Lineage - physiology; Cell Tracking; Diabetes; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryos; Experiments; Female; Fluorescence; Gene expression; Gene Expression Regulation; Genes, Reporter; Gestation; Homeobox Protein Nkx-2.2; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Insulin; Insulin Resistance; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Medicine; Medicine and Health Sciences; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NeuroD protein; Neurogenins; Nkx2.2 protein; Nuclear Proteins; Pancreas; Pediatrics; Pregnancy; Red Fluorescent Protein; Regulatory Factor X Transcription Factors; Reproduction (copying); Research and Analysis Methods; Rodents; Signal Transduction; Sox9 protein; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Transcription Factor HES-1; Transcription Factors - genetics; Transcription Factors - metabolism; Transgenic animals; Womens health; Zebrafish Proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100398

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.