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

• Published in: Science advances 2020-11, Vol.6 (47)
• Main Authors: Yang, Kisuk, Lee, Miseon, Jones, Peter Anthony, Liu, Sophie S, Zhou, Angela, Xu, Jun, Sreekanth, Vedagopuram, Wu, Jamie L Y, Vo, Lillian, Lee, Eunjee A, Pop, Ramona, Lee, Yuhan, Wagner, Bridget K, Melton, Douglas A, Choudhary, Amit, Karp, Jeffrey M
• Format: Article
• Language: English
• Subjects: Applied Sciences and Engineering; Cell Culture Techniques - methods; Cell Proliferation; Chemistry; Diabetes Mellitus, Type 2; Engineering; Humans; Prodrugs - pharmacology; SciAdv r-articles; Zinc
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abc3207

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.