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Charting cellular identity during human in vitro β-cell differentiation

机译：在人体外β细胞分化期间图表细胞同一性

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摘要

In vitro differentiation of human stem cells can produce pancreatic beta-cells; the loss of this insulin-secreting cell type underlies type 1 diabetes. Here, as a step towards understanding this differentiation process, we report the transcriptional profiling of more than 100,000 human cells undergoing in vitro beta-cell differentiation, and describe the cells that emerged. We resolve populations that correspond to beta-cells, alpha-like poly-hormonal cells, non-endocrine cells that resemble pancreatic exocrine cells and a previously unreported population that resembles enterochromaffin cells. We show that endocrine cells maintain their identity in culture in the absence of exogenous growth factors, and that changes in gene expression associated with in vivo beta-cell maturation are recapitulated in vitro. We implement a scalable re-aggregation technique to deplete non-endocrine cells and identify CD49a (also known as ITGA1) as a surface marker of the beta-cell population, which allows magnetic sorting to a purity of 80%. Finally, we use a high-resolution sequencing time course to characterize gene-expression dynamics during the induction of human pancreatic endocrine cells, from which we develop a lineage model of in vitro beta-cell differentiation. This study provides a perspective on human stem-cell differentiation, and will guide future endeavours that focus on the differentiation of pancreatic islet cells, and their applications in regenerative medicine.
机译：人干细胞的体外分化可以产生胰腺β细胞;这种胰岛素分泌细胞类型的丧失是1型糖尿病。在这里，作为理解这种分化过程的一步，我们报告了在体外β细胞分化中进行了超过100,000名人体细胞的转录分析，并描述了出现的细胞。我们解决与β-细胞，类似α样多环群细胞，类似胰腺外分泌细胞的非内分泌细胞的群体以及先前未报告的群体类似于肠溶细胞细胞的群体。我们表明内分泌细胞在没有外源生长因子的情况下保持其在培养方面的身份，并且在体外重新携带与体内β细胞成熟相关的基因表达的变化。我们实施一种可扩展的重新聚集技术来耗尽非内分泌细胞，并将CD49a（也称为Itga1）鉴定为β细胞群的表面标志物，这允许磁性分选至80％的纯度。最后，我们使用高分辨率测序时间过程来表征在诱导人胰腺内分泌细胞期间的基因表达动态，从中开发了体外β细胞分化的谱系模型。本研究提供了对人体干细胞分化的观点，并将引导未来的努力，这些努力关注胰岛细胞的分化，以及它们在再生医学中的应用。

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  • 来源
    《Nature》 |2019年第7756期|368-373|共6页
  • 作者

    Veres Adrian; Faust Aubrey L.; Bushnell Henry L.; Engquist Elise N.; Kenty Jennifer Hyoje-Ryu; Harb George; Poh Yeh-Chuin; Sintov Elad; Gurtler Mads; Pagliuca Felicia W.; Peterson Quinn P.; Melton Douglas A.;

  • 作者单位

    Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA|Harvard Univ Harvard Stem Cell Inst Cambridge MA 02138 USA|MIT Harvard Mit Div Hlth Sci & Technol Cambridge MA 02139 USA|Harvard Univ Harvard Syst Biol PhD Program Cambridge MA 02138 USA;

    Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA|Harvard Univ Harvard Stem Cell Inst Cambridge MA 02138 USA;

    Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA|Harvard Univ Harvard Stem Cell Inst Cambridge MA 02138 USA;

    Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA|Harvard Univ Harvard Stem Cell Inst Cambridge MA 02138 USA;

    Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA;

    Semma Therapeut Cambridge MA USA;

    Semma Therapeut Cambridge MA USA;

    Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA|Harvard Univ Harvard Stem Cell Inst Cambridge MA 02138 USA;

    Semma Therapeut Cambridge MA USA;

    Semma Therapeut Cambridge MA USA;

    Mayo Clin Dept Physiol & Biomed Engn Rochester MN USA;

    Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA|Harvard Univ Harvard Stem Cell Inst Cambridge MA 02138 USA|Howard Hughes Med Inst Chevy Chase MD 20815 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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