Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Nguyen Ngoc, K. V.; Sai, S.; Jun, Y.; Bender, R. H. F.; Kravets, V.; Zhu, H.; Hatch, C. J.; Schlichting, M.; Gaetani, R.; Mallick, M.; Hachey, S. J.; Christman, K.; George, S. C.; Hughes, C. C.; Sander, M.

doi:10.1101/2022.10.28.513298

bioRxiv · 10.1101/2022.10.28.513298

Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Nguyen Ngoc, K. V.·Sai, S.·Jun, Y.·Bender, R. H. F.·Kravets, V.·Zhu, H.·Hatch, C. J.·Schlichting, M.·Gaetani, R.·Mallick, M.·Hachey, S. J.·Christman, K.·George, S. C.·Hughes, C. C.·Sander, M.

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Abstract

Blood vessels play a critical role in pancreatic islet health and function, yet current culture methods to generate islet organoids from human pluripotent stem cells (SC-islets) lack a vascular component. Here, we engineered 3D vascularized SC-islet organoids by assembling SC-islet cells, human primary endothelial cells (ECs) and fibroblasts both in a non-perfused model and a microfluidic device with perfused vessels. Vasculature improved stimulus-dependent Ca2+ influx into SC-{beta}-cells, a hallmark of {beta}-cell function that is blunted in non-vascularized SC-islets. We show that an islet-like basement membrane is formed by vasculature and contributes to the functional improvement of SC-{beta}-cells. Furthermore, cell-cell communication networks based on scRNA-seq data predicted BMP2/4-BMPR2 signaling from ECs to SC-{beta}-cells. Correspondingly, BMP4 augmented the SC-{beta}-cell Ca2+ response and insulin secretion. These vascularized SC-islet models will enable further studies of crosstalk between {beta}-cells and ECs and can serve as in vivo-mimicking platforms for disease modeling and therapeutic testing.

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Nguyen Ngoc, K. V., Sai, S., Jun, Y., Bender, R. H. F., Kravets, V., Zhu, H., Hatch, C. J., Schlichting, M., Gaetani, R., Mallick, M., Hachey, S. J., Christman, K., George, S. C., Hughes, C. C., Sander, M.. 2022-10-30. Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids. https://doi.org/10.1101/2022.10.28.513298

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