美国华盛顿大学医学院Jeffrey R. Millman小组的研究利用单核多组学揭示了人干细胞来源胰岛谱系的特异性缺陷。2023年5月15日出版的《自然—细胞生物学》发表了这项成果。

为了更好地了解SC胰岛内细胞类型的状态并确定谱系特异性缺陷，研究人员使用单核多组学测序来分析SC胰岛和原代人胰岛细胞的染色质可及性和转录谱。

研究人员开发出一种分析方法，与原代胰岛相比能够衍生出基因列表和活性，以鉴定每种SC胰岛细胞类型。在SC胰岛中，研究发现β细胞和肠嗜铬样细胞之间的差异是由细胞状态梯度而非细胞身份的明显差异造成。

此外，体内SC胰岛移植随着时间的推移改善了细胞特征，而长期体外培养则没有。总的来说，该研究结果揭示了染色质和转录图谱在胰岛细胞发育和成熟过程中的重要作用。

据介绍，人多能干细胞来源的能产生胰岛素的β细胞具有治疗胰岛素依赖性糖尿病的潜力，但人多能干细胞来源的胰岛（SC胰岛）仍然与人体自身胰岛细胞不同。

附：英文原文

Title: Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification

Author: Augsornworawat, Punn, Hogrebe, Nathaniel J., Ishahak, Matthew, Schmidt, Mason D., Marquez, Erica, Maestas, Marlie M., Veronese-Paniagua, Daniel A., Gale, Sarah E., Miller, Julia R., Velazco-Cruz, Leonardo, Millman, Jeffrey R.

Issue&Volume: 2023-05-15

Abstract: 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.

DOI: 10.1038/s41556-023-01150-8

Source: https://www.nature.com/articles/s41556-023-01150-8