Liver regeneration is a well-orchestrated process that is typically studied in animal models. Although previous animal studies have offered many insights into liver regeneration, human biology is less well understood. To this end, we developed a three-dimensional (3D) platform called structurally vascularized hepatic ensembles for analyzing regeneration (SHEAR) to model multiple aspects of human liver regeneration. SHEAR enables control over hemodynamic alterations to mimic those that occur during liver injury and regeneration and supports the administration of biochemical inputs such as cytokines and paracrine interactions with endothelial cells. We found that exposing the endothelium-lined channel to fluid flow led to increased secretion of regeneration-associated factors. Stimulation with relevant cytokines not only amplified the secretory response, but also induced cell-cycle entry of primary human hepatocytes (PHHs) embedded within the device. Further, we identified endothelial-derived mediators that are sufficient to initiate proliferation of PHHs in this context. Collectively, the data presented here underscore the importance of multicellular models that can recapitulate high-level tissue functions and demonstrate that the SHEAR device can be used to discover and validate conditions that promote human liver regeneration.

中文翻译：

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人类肝脏的血管模型模拟再生反应

肝脏再生是一个精心策划的过程，通常在动物模型中进行研究。尽管之前的动物研究提供了许多关于肝脏再生的见解，但人类生物学却知之甚少。为此，我们开发了一个三维（3D）平台，称为结构血管化肝整体再生分析（SHEAR），以模拟人类肝脏再生的多个方面。SHEAR 能够控制血流动力学变化，以模拟肝损伤和再生过程中发生的变化，并支持细胞因子和旁分泌与内皮细胞相互作用等生化输入的管理。我们发现，将内皮细胞通道暴露于流体流动会导致再生相关因子的分泌增加。相关细胞因子的刺激不仅放大了分泌反应，而且还诱导了嵌入装置内的原代人肝细胞（PHH）进入细胞周期。此外，我们还确定了在这种情况下足以启动 PHH 增殖的内皮源性介质。总的来说，这里提供的数据强调了多细胞模型的重要性，该模型可以概括高水平的组织功能，并证明 SHEAR 设备可用于发现和验证促进人类肝脏再生的条件。