Panday Regeant, Monckton Chase P, Khetani Salman R
Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois.
Semin Liver Dis. 2022 Feb;42(1):1-16. doi: 10.1055/s-0041-1742279. Epub 2022 Feb 4.
As blood flows from the portal triad to the central vein, cell-mediated depletion establishes gradients of soluble factors such as oxygen, nutrients, and hormones, which act through molecular pathways (e.g., Wnt/β-catenin, hedgehog) to spatially regulate hepatocyte functions along the sinusoid. Such "zonation" can lead to the compartmentalized initiation of several liver diseases, including alcoholic/non-alcoholic fatty liver diseases, chemical/drug-induced toxicity, and hepatocellular carcinoma, and can also modulate liver regeneration. Transgenic rodent models provide valuable information on the key molecular regulators of zonation, while in vitro models allow for subjecting cells to precisely controlled factor gradients and elucidating species-specific differences in zonation. Here, we discuss the latest advances in both in vivo and in vitro models of liver zonation and pending questions to be addressed moving forward. Ultimately, obtaining a deeper understanding of zonation can lead to the development of more effective therapeutics for liver diseases, microphysiological systems, and scalable cell-based therapies.
当血液从门静脉三联体流向中央静脉时，细胞介导的消耗建立了诸如氧气、营养物质和激素等可溶性因子的梯度，这些因子通过分子途径（如Wnt/β-连环蛋白、刺猬信号通路）发挥作用，在空间上沿肝血窦调节肝细胞功能。这种“区域化”可导致包括酒精性/非酒精性脂肪性肝病、化学/药物诱导的毒性以及肝细胞癌在内的多种肝脏疾病的分区起始，还可调节肝脏再生。转基因啮齿动物模型提供了关于区域化关键分子调节因子的有价值信息，而体外模型则允许使细胞暴露于精确控制的因子梯度下，并阐明区域化中的物种特异性差异。在此，我们讨论肝脏区域化体内和体外模型的最新进展以及未来有待解决的问题。最终，更深入地了解区域化可推动开发针对肝脏疾病、微生理系统和可扩展的细胞疗法的更有效治疗方法。
