Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0653, USA; Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA.
Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Dev Cell. 2023 May 8;58(9):727-743.e11. doi: 10.1016/j.devcel.2023.03.011. Epub 2023 Apr 10.
Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-β cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β cell maturation and identify sex hormones as drivers of β cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.
人多能干细胞衍生的胰岛细胞在糖尿病建模和治疗方面具有巨大的应用前景。干细胞衍生的胰岛与原代胰岛之间仍然存在差异，但目前用于指导改进的分子见解有限。在这里，我们在体外胰岛分化过程中以及来自儿童和成人供体的胰腺中获得了单细胞转录组和可及染色质图谱，以便进行比较。我们描绘了主要的细胞类型，定义了它们的调控网络，并描述了转录因子之间的时空基因调控关系。CDX2 作为肠嗜铬样细胞的调节因子出现，我们发现它类似于胎儿胰腺中短暂的、以前未被识别的、产生 5-羟色胺的前 β 细胞群，这反驳了之前提出的非胰腺起源假说。此外，我们在体外 β 细胞成熟过程中观察到信号依赖性转录程序的激活不足，并确定了性激素是儿童时期 β 细胞增殖的驱动因素。总的来说，我们的分析提供了对干细胞衍生胰岛中细胞命运获得的全面理解，并为操纵细胞身份和成熟提供了一个框架。
