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-3 A stem cell system reveals islet formation through an unidentified budding process

Jia Zhao, Canada

The University of British Columbia
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A stem cell system reveals islet formation through an unidentified budding process

Jia Zhao1, Shenghui Liang1, Howard Cen1, Robert Baker1, Yanjun Li2, Huixia Ren2, Liangyi Chen2, Yanmei Liu2, James Johnson1, Timothy Kieffer1.

1Cellular & Physiological Sciences, The University of British Columbia, Vancouver, BC, Canada; 2Institute of Molecular Medicine, Peking University, Beijing, People's Republic of China

Introduction: Although diabetes results from the selective demise of insulin-producing beta cells, a cell-based therapy with a mixed cell population that works as a functional unit, will likely be most effective. Indeed, across species, islets are comprised of a mixture of endocrine cell types, often in different proportions and arrangements. However, the developmental mechanisms responsible, particularly in humans, remain poorly understood, hampering efforts to optimize the production of fully mature islets from stem cells.
Method: By fine-tuned differentiation conditions at early stage, we developed a strategy to generate islet organoids that are enriched for major islet cell types. 
Results: We observe “bud structures” developing from progenitor cells that progressively expand into islet organoids in a process that may resemble natural islet development and/or regeneration. Specifically, our characterization indicates that spontaenous clustering of a subset of progenitor cells may contribute to budding structure formation and facilitate subsequent endocrine cell commitment. Interestingly, during the endocrine induction in our islet organoid system, we initially observed a mixed organization of early endocrine cells that resembles a human islet-like architecture with cells seemingly randomly dispersed throughout the islet; while at the more matured stage, islet organoids adopted a mouse islet-like architecture with a core-mantle organization of beta cells in the center and alpha cells in the periphery. Along with islet cell remodeling, we also observed functional development (glucose regulated insulin secretion) within the heterogeneous population of these differentiated islet organoids.
Conclusion: Our islet budding model provides new opportunities to understand human islet development and could guide further optimization of islet manufacturing from stem cells. Our work to explore islet cell organization could also inform future attempts to engineer stem cell-derived islets with optimal cytoarchitecture and robust insulin production.

Michael Smith Health Research BC. JDRF. CIHR.


[1] Rezania, A., Bruin, J.E., Arora, P., Rubin, A., Batushansky, I., Asadi, A., O'Dwyer, S., Quiskamp, N., Mojibian, M., Albrecht, T., et al. (2014). Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32, 1121-1133. 10.1038/nbt.3033.
[2] Zhao, J., Liang, S., Zhao, Y., Zong, W., Tran, E., Chen, L., and Liu, Y. (2021). In vivo Imaging of Calcium Activities from Pancreatic beta-cells in Zebrafish Embryos Using Spinning-disc Confocal and Two-photon Light-sheet Microscopy. Bio Protoc 11, e4245. 10.21769/BioProtoc.4245.
[3] Sharon, N. et al. (2019). A peninsular structure coordinates asynchronous differentiation with morphogenesis to generate pancreatic islets. Cell, 2018.12.003

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