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.

治疗 β 细胞丢失的进展包括胰岛替代疗法或分别增加 1 型和 2 型糖尿病的细胞增殖率。我们建议开发多种靶向 β 细胞中高浓度锌离子的增殖诱导前药。不幸的是，典型的二维 (2D) 细胞培养不能模拟体内条件，锌含量显着降低，而 3D 培养系统既费力又昂贵。因此，我们开发了 Disque Platform (DP)——一种高保真培养系统，其中干细胞衍生的 β 细胞在 2D 96 孔板中重新聚集成薄的 3D 圆盘。我们针对标准 2D 和 3D 培养物验证了 DP，并询问了我们的锌激活前药，它们在锌螯合时释放它们的货物 - 因此优先在 β 细胞中。