A pro-endocrine pancreatic transcriptional program established during development is retained in human gallbladder epithelial cells

Joglekar, M. V.; Sahu, S.; Wong, W. K. M.; Satoor, S. N.; Dong, C. X.; Farr, R. J.; Williams, M. D.; Pandya, P.; Jhala, G.; Yang, S. N. Y.; Chew, Y. V.; Hetherington, N.; Thiruchevlam, D.; Mitnala, S.; Rao, G. V.; Reddy, D. N.; Loudovaris, T.; Hawthorne, W. J.; Elefanty, A. G.; Joglekar, V. M.; Stanley, E. G.; Martin, D.; Thomas, H. E.; Tosh, D.; Dalgaard, L. T.; Hardikar, A. A.

doi:10.1101/2021.03.02.433636

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bioRxiv · 10.1101/2021.03.02.433636

A pro-endocrine pancreatic transcriptional program established during development is retained in human gallbladder epithelial cells

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Abstract

ObjectivePancreatic islet {beta}-cells are factories for insulin production; however ectopic expression of insulin is also well recognized. The gallbladder is a next-door neighbour to the developing pancreas. Here, we wanted to understand if gallbladders contain functional insulin-producing cells. DesignWe compared developing and adult mouse as well as human gallbladder epithelial cells and islets using immunohistochemistry, flow cytometry, ELISAs, RNA-sequencing, real-time PCR, chromatin immunoprecipitation and functional studies. ResultsWe demonstrate 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 for the first time 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 NOD mouse model of type 1 diabetes, we observed that insulin-producing cells in the gallbladder are not targeted by autoimmune cells. Conclusion: In summary, our biochemical, transcriptomic, and functional data in human gallbladder epithelial cells collectively demonstrate their potential for insulin-production under pathophysiological conditions, and open newer areas for type 1 diabetes research and therapy. Significance of the study What is already known about this subject?O_LIDeveloping pancreas and gallbladder are next-door neighbours and share similar developmental pathways. C_LIO_LIHuman Gallbladder-derived progenitor cells were shown to differentiate into insulin-producing cells. C_LI What are the new findings?O_LIGallbladder epithelium contains interspersed cells that can transcribe, translate, package and secrete insulin. C_LIO_LIInsulin-producing cells in the gallbladder are not destroyed by immune cells in an animal model of type 1 diabetes (T1D). C_LIO_LIOur studies demonstrating the absence of insulin splice variants in human gallbladder cells, and higher splice forms in human islets, suggest a potential mechanism (via defective ribosomal products) in escaping islet autoimmunity. C_LI How might it impact clinical practice?O_LIDeciphering mechanisms of protection of insulin-producing cells from immune cells in the gallbladder could help in developing strategies to prevent islet autoimmunity in T1D. C_LI

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Joglekar, M. V., Sahu, S., Wong, W. K. M., Satoor, S. N., Dong, C. X., Farr, R. J., Williams, M. D., Pandya, P., Jhala, G., Yang, S. N. Y., Chew, Y. V., Hetherington, N., Thiruchevlam, D., Mitnala, S., Rao, G. V., Reddy, D. N., Loudovaris, T., Hawthorne, W. J., Elefanty, A. G., Joglekar, V. M., Stanley, E. G., Martin, D., Thomas, H. E., Tosh, D., Dalgaard, L. T., Hardikar, A. A.. 2021-03-02. A pro-endocrine pancreatic transcriptional program established during development is retained in human gallbladder epithelial cells. https://doi.org/10.1101/2021.03.02.433636

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