A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells

Science Advances
Kisuk YangJeffrey M Karp

Abstract

Advances in treating β cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in β cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)-a high-fidelity culture system where stem cell-derived β cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation-so preferentially in β cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in β cell proliferation compared to harmine.

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Citations

Mar 16, 2021·Frontiers in Endocrinology·Amanda Oakie, Maria Cristina Nostro
Sep 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Kisuk YangJeffrey M Karp

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Methods Mentioned

BETA
confocal microscopy
flow cytometry
nuclear translocation
enzyme-linked immunosorbent assay
Assay
ELISA

Software Mentioned

ImageJ
GraphPad Prism
FlowJo
Adobe Photoshop

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