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Pancreatic Pseudoislets: An Organoid Archetype for Metabolism Research

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posted on 04.05.2021, 18:34 by Mollie S.H. Friedlander, Vy M. Nguyen, Seung K. Kim, Romina J. Bevacqua
Pancreatic islets are vital endocrine regulators of systemic metabolism, and recent investigations have increasingly focused on understanding human islet biology. Studies of isolated human islets have advanced understanding of the development, function, and regulation of cells comprising islets, especially pancreatic α- and β-cells. However, the multicellularity of the intact islet has stymied specific experimental approaches—particularly in genetics and cell signaling interrogation. This barrier has been circumvented by the observation that islet cells can survive dispersion and reaggregate to form ‘pseudoislets’, organoids that retain crucial physiological functions, including regulated insulin and glucagon secretion. Recently, exciting advances in the use of pseudoislets for genetics, genomics, islet cell transplantation, and studies of intra-islet signaling and islet cell interactions have been reported by investigators worldwide. Here we review molecular and cellular mechanisms thought to promote islet cell reaggregation, summarize methods that optimize pseudoislet development, and detail recent insights about human islet biology from genetic and transplantation-based pseudoislet experiments. Owing to robust, international programs for procuring primary human pancreata, pseudoislets should serve as both a durable paradigm for primary organoid studies and as an engine of discovery for islet biology, diabetes, and metabolism research.

Funding

M.S.H.F. is a student in the Stanford Medical Scientist Training Program and Knight-Hennessey Scholars Program, and was supported by the Stanford Medical Scholars Program and Howard Hughes Medical Institute Medical Research Fellows Program. V.M.N. was supported by a NIH T32 training grant (5T32GM007790). R.J.B. was supported by a postdoctoral fellowship from JDRF (3-PDF-2018-584-A-N) and is on leave from the Animal Biotechnology Laboratory, Facultad de Agronomía, Universidad de Buenos Aires/INPA CONICET, CABA, Argentina. Work here was supported by NIH awards (R01 DK107507; R01 DK108817; U01 DK123743; R01DK126482 to S.K.K.; R01DK116782 to P. Bollyky), and JDRF Center of Excellence (to S.K.K. and M. Hebrok). Work here was also supported by NIH grant P30 DK116074 (S.K.K.), by the Snyder Foundation and Elser Trust, and by the Stanford Islet Research Core and Diabetes Genomics and Analysis Core of the Stanford Diabetes Research Center.

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