Insulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived islets (SC-islets) still differ from their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility and transcriptional profiles of SC-islets and primary human islets. Here we provide an analysis that enabled the derivation of gene lists and activity for identifying each SC-islet cell type compared with primary islets. Within SC-islets, we found that the difference between β cells and awry enterochromaffin-like cells is a gradient of cell states rather than a stark difference in identity. Furthermore, transplantation of SC-islets in vivo improved cellular identities overtime, while long-term in vitro culture did not. Collectively, our results highlight the importance of chromatin and transcriptional landscapes during islet cell specification and maturation.

由人类多能干细胞产生的产生胰岛素的β细胞具有治疗胰岛素依赖性糖尿病的潜力，但人类多能干细胞衍生的胰岛（SC-胰岛）仍然与其体内对应物不同。为了更好地了解 SC 胰岛内细胞类型的状态并识别谱系规范缺陷，我们使用单核多组学测序来分析 SC 胰岛和原代人类胰岛的染色质可及性和转录谱。在这里，我们提供了一种分析，可以推导基因列表和活性，以识别与原代胰岛相比的每种 SC 胰岛细胞类型。在 SC 胰岛中，我们发现 β 细胞和错误的肠嗜铬样细胞之间的差异是细胞状态的梯度，而不是身份上的明显差异。此外，随着时间的推移，体内 SC 胰岛移植可以改善细胞特性，而长期体外培养却不能。总的来说，我们的结果强调了染色质和转录景观在胰岛细胞规范和成熟过程中的重要性。