Transcriptional Heterogeneity of Beta Cells in the Intact Pancreas

• Published in: Developmental cell Vol. 48; no. 1; pp. 115 - 125.e4
• Main Authors: Farack, Lydia, Golan, Matan, Egozi, Adi, Dezorella, Nili, Bahar Halpern, Keren, Ben-Moshe, Shani, Garzilli, Immacolata, Tóth, Beáta, Roitman, Lior, Krizhanovsky, Valery, Itzkovitz, Shalev
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-01-2019
• Subjects: Animals; beta cell heterogeneity; diabetes; Diabetes Mellitus, Experimental - metabolism; Genetic Heterogeneity; Glucose - metabolism; Insulin - metabolism; insulin secretion; Insulin Secretion - physiology; Insulin-Secreting Cells - metabolism; Islets of Langerhans - metabolism; Mice, Transgenic; mRNA polarization; pancreas; Pancreas - metabolism; Proinsulin - metabolism; RNA intracellular localization; single molecule Fluorescence in-situ Hybridization; single molecule Fluorescence in-situ Hybridization; pancreas; mRNA polarization; insulin secretion; diabetes; RNA intracellular localization; beta cell heterogeneity
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2018.11.001

Pancreatic beta cells have been shown to be heterogeneous at multiple levels. However, spatially interrogating transcriptional heterogeneity in the intact tissue has been challenging. Here, we developed an optimized protocol for single-molecule transcript imaging in the intact pancreas and used it to identify a sub-population of “extreme” beta cells with elevated mRNA levels of insulin and other secretory genes. Extreme beta cells contain higher ribosomal and proinsulin content but lower levels of insulin protein in fasted states, suggesting they may be tuned for basal insulin secretion. They exhibit a distinctive intra-cellular polarization pattern, with elevated mRNA concentrations in an apical ER-enriched compartment, distinct from the localization of nascent and mature proteins. The proportion of extreme cells increases in db/db diabetic mice, potentially facilitating the required increase in basal insulin. Our results thus highlight a sub-population of beta cells that may carry distinct functional roles along physiological and pathological timescales.
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•Islets contain a minority of “extreme” beta cells with elevated insulin mRNA levels•Elevated proinsulin yet lower insulin protein suggests these are basal secretors•Extreme cells exhibit discordant apical-basal mRNA and protein localization•The proportion of extreme cells increases in insulin-resistant animals
Using an optimized protocol for single-molecule transcript imaging of the intact pancreas, Farack, Golan, et al. reveal that a small subset of beta cells harbors elevated levels of ribosomes and insulin mRNA, suggesting a sub-specialization in basal insulin secretion.