A Pro-Endocrine Pancreatic Islet Transcriptional Program Established During Development Is Retained in Human Gallbladder Epithelial Cells

Mugdha V. Joglekar, Subhshri Sahu, Wilson K.M. Wong, Sarang N. Satoor, Charlotte X. Dong, Ryan J. Farr, Michael D. Williams, Prapti Pandya, Gaurang Jhala, Sundy N.Y. Yang, Yi Vee Chew, Nicola Hetherington, Dhan Thiruchevlam, Sasikala Mitnala, Guduru V. Rao, Duvvuru Nageshwar Reddy, Thomas Loudovaris, Wayne J. Hawthorne, Andrew G. Elefanty, Vinay M. JoglekarEdouard G. Stanley, David Martin, Helen E. Thomas, David Tosh, Louise T. Dalgaard, Anandwardhan A. Hardikar

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: Pancreatic islet β-cells are factories for insulin production; however, ectopic expression of insulin also is well recognized. The gallbladder is a next-door neighbor to the developing pancreas. Here, we wanted to understand if gallbladders contain functional insulin-producing cells. Methods: We compared developing and adult mouse as well as human gallbladder epithelial cells and islets using immunohistochemistry, flow cytometry, enzyme-linked immunosorbent assays, RNA sequencing, real-time polymerase chain reaction, chromatin immunoprecipitation, and functional studies. Results: We show that the epithelial lining of developing, as well as adult, mouse and human gallbladders naturally contain interspersed cells that retain the capacity to actively transcribe, translate, package, and release insulin. We show that human gallbladders also contain functional insulin-secreting cells with the potential to naturally respond to glucose in vitro and in situ. Notably, in a non-obese diabetic (NOD) mouse model of type 1 diabetes, we observed that insulin-producing cells in the gallbladder are not targeted by autoimmune cells. Interestingly, in human gallbladders, insulin splice variants are absent, although insulin splice forms are observed in human islets. Conclusions: In summary, our biochemical, transcriptomic, and functional data in mouse and human gallbladder epithelial cells collectively show the evolutionary and developmental similarities between gallbladder and the pancreas that allow gallbladder epithelial cells to continue insulin production in adult life. Understanding the mechanisms regulating insulin transcription and translation in gallbladder epithelial cells would help guide future studies in type 1 diabetes therapy.

Original languageEnglish (US)
Pages (from-to)1530-1553.e4
JournalCMGH
Volume13
Issue number5
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • Differentiation
  • Gallbladder Development
  • Insulin
  • Islets
  • Splice Variants

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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