Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Nat Rev Gastroenterol Hepatol. 2019 Jul;16(7):395-410. doi: 10.1038/s41575-019-0134-x.
Hepatocytes operate in highly structured repeating anatomical units termed liver lobules. Blood flow along the lobule radial axis creates gradients of oxygen, nutrients and hormones, which, together with morphogenetic fields, give rise to a highly variable microenvironment. In line with this spatial variability, key liver functions are expressed non-uniformly across the lobules, a phenomenon termed zonation. Technologies based on single-cell transcriptomics have constructed a global spatial map of hepatocyte gene expression in mice revealing that ~50% of hepatocyte genes are expressed in a zonated manner. This broad spatial heterogeneity suggests that hepatocytes in different lobule zones might have not only different gene expression profiles but also distinct epigenetic features, regenerative capacities, susceptibilities to damage and other functional aspects. Here, we present genomic approaches for studying liver zonation, describe the principles of liver zonation and discuss the intrinsic and extrinsic factors that dictate zonation patterns. We also explore the challenges and solutions for obtaining zonation maps of liver non-parenchymal cells. These approaches facilitate global characterization of liver function with high spatial resolution along physiological and pathological timescales.
肝细胞在称为肝小叶的高度结构化重复解剖单位中发挥作用。沿着小叶放射轴的血流产生氧气、营养物质和激素的梯度，这些与形态发生场一起，产生高度可变的微环境。与这种空间变异性一致，关键的肝脏功能在整个小叶中不均匀表达，这种现象称为分区。基于单细胞转录组学的技术构建了小鼠肝细胞基因表达的全局空间图谱，揭示了约 50%的肝细胞基因以分区方式表达。这种广泛的空间异质性表明，不同小叶区的肝细胞不仅可能具有不同的基因表达谱，而且具有不同的表观遗传特征、再生能力、易损性和其他功能方面。在这里，我们介绍了研究肝分区的基因组方法，描述了肝分区的原则，并讨论了决定分区模式的内在和外在因素。我们还探讨了获得肝非实质细胞分区图谱的挑战和解决方案。这些方法促进了在生理和病理时间尺度上以高空间分辨率对肝脏功能进行全面表征。
