Different developmental histories of beta-cells generate functional and proliferative heterogeneity during islet growth

• Published in: Nature communications 2017-09, Vol.8 (1), p.664-16, Article 664
• Main Authors: Singh, Sumeet Pal, Janjuha, Sharan, Hartmann, Theresa, Kayisoglu, Özge, Konantz, Judith, Birke, Sarah, Murawala, Priyanka, Alfar, Ezzaldin Ahmed, Murata, Kei, Eugster, Anne, Tsuji, Naoki, Morrissey, Edward R., Brand, Michael, Ninov, Nikolay
• Format: Article
• Language: English
• Subjects: 631/136/142; 631/1647/334/1874/763; 692/4020/2741/416; Animals; Animals, Genetically Modified; Beta cells; Birth; Calcium; Calcium imaging; Cell Lineage; Cell Proliferation; Cytological Techniques - methods; Danio rerio; Developmental stages; Embryo, Nonmammalian - cytology; Embryo, Nonmammalian - drug effects; Embryogenesis; Glucose; Glucose - metabolism; Heterogeneity; Humanities and Social Sciences; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Islets of Langerhans - cytology; Islets of Langerhans - embryology; Mathematical morphology; multidisciplinary; Pancreas; Science; Science (multidisciplinary); Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; Urocortins - metabolism; Zebrafish; Zebrafish - embryology; Zebrafish - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00461-3

The proliferative and functional heterogeneity among seemingly uniform cells is a universal phenomenon. Identifying the underlying factors requires single-cell analysis of function and proliferation. Here we show that the pancreatic beta-cells in zebrafish exhibit different growth-promoting and functional properties, which in part reflect differences in the time elapsed since birth of the cells. Calcium imaging shows that the beta-cells in the embryonic islet become functional during early zebrafish development. At later stages, younger beta-cells join the islet following differentiation from post-embryonic progenitors. Notably, the older and younger beta-cells occupy different regions within the islet, which generates topological asymmetries in glucose responsiveness and proliferation. Specifically, the older beta-cells exhibit robust glucose responsiveness, whereas younger beta-cells are more proliferative but less functional. As the islet approaches its mature state, heterogeneity diminishes and beta-cells synchronize function and proliferation. Our work illustrates a dynamic model of heterogeneity based on evolving proliferative and functional beta-cell states. Βeta-cells have recently been shown to be heterogeneous with regard to morphology and function. Here, the authors show that β-cells in zebrafish switch from proliferative to functional states with increasing time since β-cell birth, leading to functional and proliferative heterogeneity.