人多能干细胞源性咽前肠内胚层的生成与分子特征。
Generation and molecular characterization of human pluripotent stem cell-derived pharyngeal foregut endoderm.
机构信息
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Department of Psychiatry, University of Münster, Münster, Germany.
出版信息
Dev Cell. 2023 Sep 25;58(18):1801-1818.e15. doi: 10.1016/j.devcel.2023.08.024.
Approaches to study human pharyngeal foregut endoderm-a developmental intermediate that is linked to various human syndromes involving pharynx development and organogenesis of tissues such as thymus, parathyroid, and thyroid-have been hampered by scarcity of tissue access and cellular models. We present an efficient stepwise differentiation method to generate human pharyngeal foregut endoderm from pluripotent stem cells. We determine dose and temporal requirements of signaling pathway engagement for optimized differentiation and characterize the differentiation products on cellular and integrated molecular level. We present a computational classification tool, "CellMatch," and transcriptomic classification of differentiation products on an integrated mouse scRNA-seq developmental roadmap confirms cellular maturation. Integrated transcriptomic and chromatin analyses infer differentiation stage-specific gene regulatory networks. Our work provides the method and integrated multiomic resource for the investigation of disease-relevant loci and gene regulatory networks and their role in developmental defects affecting the pharyngeal endoderm and its derivatives.
研究人类咽前内胚层（pharyngeal foregut endoderm）的方法——一种与涉及咽发育和胸腺、甲状旁腺和甲状腺等组织器官发生的各种人类综合征相关的发育中间产物——受到组织获取和细胞模型稀缺的阻碍。我们提出了一种有效的逐步分化方法，可从多能干细胞中生成人类咽前内胚层。我们确定了信号通路参与的剂量和时间要求，以实现优化的分化，并在细胞和综合分子水平上对分化产物进行特征描述。我们提出了一种计算分类工具“CellMatch”，并对分化产物进行转录组分类，整合了小鼠 scRNA-seq 发育路线图以确认细胞成熟度。综合转录组和染色质分析推断出分化阶段特异性基因调控网络。我们的工作为研究与疾病相关的基因座和基因调控网络及其在影响咽内胚层及其衍生物的发育缺陷中的作用提供了方法和综合多组学资源。
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