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Systematically labeling developmental stage-specific genes for the study of pancreatic β-cell differentiation from human embryonic stem cells FREE

机译：系统地标记发育阶段特异性基因，用于研究人类胚胎干细胞的胰腺β细胞分化

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The applications of human pluripotent stem cell (hPSC)-derived cells in regenerative medicine has encountered a long-standing challenge: how can we efficiently obtain mature cell types from hPSCs? Attempts to address this problem are hindered by the complexity of controlling cell fate commitment and the lack of sufficient developmental knowledge for guiding hPSC differentiation. Here, we developed a systematic strategy to study hPSC differentiation by labeling sequential developmental genes to encompass the major developmental stages, using the directed differentiation of pancreatic β cells from hPSCs as a model. We therefore generated a large panel of pancreas-specific mono- and dual-reporter cell lines. With this unique platform, we visualized the kinetics of the entire differentiation process in real time for the first time by monitoring the expression dynamics of the reporter genes, identified desired cell populations at each differentiation stage and demonstrated the ability to isolate these cell populations for further characterization. We further revealed the expression profiles of isolated NGN3-eGFP+ cells by RNA sequencing and identified sushi domain-containing 2 (SUSD2) as a novel surface protein that enriches for pancreatic endocrine progenitors and early endocrine cells both in human embryonic stem cells (hESC)-derived pancreatic cells and in the developing human pancreas. Moreover, we captured a series of cell fate transition events in real time, identified multiple cell subpopulations and unveiled their distinct gene expression profiles, among heterogeneous progenitors for the first time using our dual reporter hESC lines. The exploration of this platform and our new findings will pave the way to obtain mature β cells in vitro.
机译：人类多能干细胞（hPSC）衍生的细胞在再生医学中的应用遇到了长期的挑战：如何从hPSC中有效地获得成熟的细胞类型？解决这一问题的尝试受到控制细胞命运承诺的复杂性以及缺乏指导hPSC分化的足够的发展知识的阻碍。在这里，我们开发了一种系统的策略，通过使用hPSCs的胰腺β细胞定向定向分化标记连续的发育基因来涵盖主要的发育阶段，从而研究hPSC的分化。因此，我们产生了一大批胰腺特异的单和双报告细胞系。通过这个独特的平台，我们通过监测报告基因的表达动态，实时地实时观察了整个分化过程的动力学，在每个分化阶段鉴定了所需的细胞群，并展示了进一步分离这些细胞群的能力。表征。我们进一步通过RNA测序揭示了分离的NGN3-eGFP +细胞的表达谱，并确定了Sushis含2（SUSD2）作为一种新型表面蛋白，可丰富人类胚胎干细胞（hESC）中的胰腺内分泌祖细胞和早期内分泌细胞。胰腺细胞和人类胰腺发育中。此外，我们首次使用我们的双重报告基因hESC系，实时捕获了一系列细胞命运转变事件，鉴定了多个细胞亚群，并揭示了它们在异源祖细胞中独特的基因表达谱。该平台的探索和我们的新发现将为体外获得成熟β细胞铺平道路。

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