Transcriptional Heterogeneity of Beta Cells in the Intact Pancreas.

Dev Cell. 2019 Jan 7;48(1):115-125.e4.

Lydia Farack¹, Matan Golan¹, Adi Egozi¹, Nili Dezorella², Keren Bahar Halpern¹, Shani Ben-Moshe¹, Immacolata Garzilli¹, Beáta Tóth¹, Lior Roitman¹, Valery Krizhanovsky¹, Shalev Itzkovitz³

1. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
2. Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 7610001, Israel.
3. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: shalev.itzkovitz@weizmann.ac.il.

Abstract

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.

Presented by Lydia Farack