Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
Center for Cell and Gene Therapy, Texas Children's Hospital, and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, 77030, USA.
Nat Commun. 2018 Aug 22;9(1):3356. doi: 10.1038/s41467-018-05740-1.
Decoding the molecular composition of individual Ngn3 + endocrine progenitors (EPs) during pancreatic morphogenesis could provide insight into the mechanisms regulating hormonal cell fate. Here, we identify population markers and extensive cellular diversity including four EP subtypes reflecting EP maturation using high-resolution single-cell RNA-sequencing of the e14.5 and e16.5 mouse pancreas. While e14.5 and e16.5 EPs are constantly born and share select genes, these EPs are overall transcriptionally distinct concomitant with changes in the underlying epithelium. As a consequence, e16.5 EPs are not the same as e14.5 EPs: e16.5 EPs have a higher propensity to form beta cells. Analysis of e14.5 and e16.5 EP chromatin states reveals temporal shifts, with enrichment of beta cell motifs in accessible regions at later stages. Finally, we provide transcriptional maps outlining the route progenitors take as they make cell fate decisions, which can be applied to advance the in vitro generation of beta cells.
解析个体 Ngn3+内分泌祖细胞 (EPs) 在胰腺形态发生过程中的分子组成，可以深入了解调节激素细胞命运的机制。在这里，我们使用 e14.5 和 e16.5 小鼠胰腺的高分辨率单细胞 RNA 测序，鉴定了群体标志物和广泛的细胞多样性，包括反映 EP 成熟的四个 EP 亚型。虽然 e14.5 和 e16.5 的 EPs 不断产生并共享特定基因，但这些 EPs 在转录水平上总体上是不同的，同时伴随着基底上皮的变化。因此，e16.5 的 EPs 与 e14.5 的 EPs 并不相同：e16.5 的 EPs 形成 beta 细胞的倾向更高。对 e14.5 和 e16.5 的 EP 染色质状态的分析显示出时间上的转变，在后期可及区域中富集了 beta 细胞的基序。最后，我们提供了转录图谱，概述了祖细胞在做出细胞命运决定时所采取的途径，这可用于推进体外生成 beta 细胞。
