Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression
Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression
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DOI：
10.1038/s41591-019-0660-7
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发表时间：
2019-12-01
期刊：
影响因子：
82.9
通讯作者：
Zerial, Marino
中科院分区：
文献类型：
--
作者：
Segovia-Miranda, Fabian;Morales-Navarrete, Hernan;Zerial, Marino
疾病的早期诊断是有效治疗疾病的关键。人体活检的组织病理学分析是诊断组织改变的金标准。然而，这种方法分辨率低，并且忽略了由功能改变引起的3D（三维）结构变化。在这里，我们应用多光子成像、三维数字重建和计算模拟来生成非酒精性脂肪性肝病（NAFLD）不同阶段人类肝脏组织的空间分辨几何和功能模型。我们确定了一组与疾病进展相关的形态学细胞和组织参数，并发现了三维胆管（BC）网络中深刻的拓扑缺陷。个性化胆道流体动力学模拟预测心周胆道压力和微胆汁淤积增加，与患者血清中胆汁淤积生物标志物升高一致。我们的人类肝组织空间分辨率模型可以通过识别定量的多参数细胞和组织特征来定义疾病进展，并为NAFLD病理生理学提供新的见解，从而有助于高清医学。
Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.