Single-cell atlas of human liver development reveals pathways directing hepatic cell fates.
Single-cell atlas of human liver development reveals pathways directing hepatic cell fates.
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人类肝脏发育的单细胞图谱揭示了指导肝细胞命运的途径。
DOI：
10.1038/s41556-022-00989-7
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发表时间：
2022
影响因子：
21.3
通讯作者：
Wesley BT
中科院分区：
文献类型：
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作者：
Wesley BT
由于影响肝脏生命功能的疾病种类繁多，人们对其进行了广泛的研究。然而，由于缺乏对人类肝脏发育的了解，治疗方面的进展一直受到阻碍。在这里，我们通过描述在单细胞分辨率下构成人类肝脏的不同细胞类型的发育轨迹来解决这一限制。这些转录分析表明，细胞间的顺序相互作用直接导致了肝细胞的功能成熟，而非实质细胞在器官发生过程中发挥了关键作用。我们利用这些信息来获得双潜能肝母细胞类有机化合物，然后利用这个模型系统来验证信号通路在肝细胞和胆管细胞规范中的重要性。对肝脏成熟的进一步了解也使识别阶段特定的转录因子能够改善由人类多能干细胞生成的肝细胞样细胞的功能。因此，我们的研究建立了一个平台，以研究指导人类肝脏发育的基本机制，并产生临床应用的细胞类型。
The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications.