The liver zonation is an important phenomenon characterized by a gradient of several functions along the liver acinus. However, this gradient remains difficult to reproduce in in‐vitro conditions, making the obtention of an in‐vitro method to recapitulate the liver zonation a challenging issue. In this study, we evaluated the spatial evolution of the transcriptome profile of human induced pluripotent stem cells (hiPSCs) differentiated toward hepatocytes‐like cells (HLCs) phenotype in a microfluidic biochip environment. Cells collected at the inlet of the biochip, where the oxygen concentration is higher, were identified by the expression of genes involved in metabolic pathways related to cellular reorganization and cell proliferation. Cells collected in the middle and at the outlet of the biochips, where oxygen concentrations are lower, were characterized by the upregulation of genes involved in cellular detoxification processes (CYP450), PPAR signaling or arginine biosynthesis. A subset of 16 transcription factors (TFs) was extracted and identified as upstream regulators to HNF1A and PPARA. These TFs are also known as regulators to target genes engaged in the Wnt/βcatenin pathway, in the TGFβ/BMP/SMAD signaling, in the transition between epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET), in the homeostasis of lipids, bile acids and carbohydrates homeostasis, in drug metabolism, in the estrogen processing and in the oxidative stress response. Overall, the analysis allowed to confirm a partial zonation‐like pattern in hiPSCs‐derived HLCs in the microfluidic biochip environment. These results provide important insights into the reproduction of liver zonation in‐vitro for a better understanding of the phenomenon.

中文翻译：

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在微流体生物芯片环境中表征源自 hiPSC 的 HLC 中的肝分区样转录组模式。

肝脏分区是一种重要的现象，其特征在于沿肝腺泡的几种功能的梯度。然而，这种梯度在体外条件下仍然难以重现，这使得获得体外方法来概括肝脏分区成为一个具有挑战性的问题。在这项研究中，我们评估了在微流体生物芯片环境中向肝细胞样细胞 (HLC) 表型分化的人类诱导多能干细胞 (hiPSC) 转录组谱的空间演化。在氧气浓度较高的生物芯片入口处收集的细胞通过与细胞重组和细胞增殖相关的代谢途径相关基因的表达来识别。收集在生物芯片中间和出口处的细胞，那里的氧气浓度较低，其特征在于参与细胞解毒过程 (CYP450)、PPAR 信号传导或精氨酸生物合成的基因的上调。提取了 16 个转录因子 (TF) 的子集，并将其鉴定为 HNF1A 和 PPARA 的上游调节因子。这些 TF 也被称为调节因子，用于靶向参与 Wnt/βcatenin 通路、TGFβ/BMP/SMAD 信号传导、上皮间充质转化 (EMT) 和间充质上皮转化 (MET) 之间的过渡、脂质稳态的基因、胆汁酸和碳水化合物稳态、药物代谢、雌激素处理和氧化应激反应。总体而言，该分析允许在微流体生物芯片环境中确认 hiPSC 衍生的 HLC 中的部分分区样模式。