The liver plays a key role in the metabolism of lipoproteins, controlling both production and catabolism. To accelerate the development of new lipid‐lowering therapies in humans, it is essential to have a relevant in vitro study model available. The current hepatocyte‐like cells (HLCs) models derived from hiPSC can be used to model many genetically driven diseases but require further improvement to better recapitulate the complexity of liver functions. Here, we aimed to improve the maturation of HLCs using a three‐dimensional (3D) approach using Biomimesys®, a hyaluronic acid‐based hydroscaffold in which hiPSCs may directly form aggregates and differentiate toward a functional liver organoid model. After a 28‐day differentiation 3D protocol, we showed that many hepatic genes were upregulated in the 3D model (liver organoids) in comparison with the 2D model (HLCs). Liver organoids, grown on Biomimesys®, exhibited an autonomous cell organization, were composed of different cell types and displayed enhanced cytochromes P450 activities compared to HLCs. Regarding the functional capacities of these organoids, we showed that they were able to accumulate lipids (hepatic steatosis), internalize low‐density lipoprotein and secrete apolipoprotein B. Interestingly, we showed for the first time that this model was also able to produce apolipoprotein (a), the apolipoprotein (a) specific of Lp(a). This innovative hiPSC‐derived liver organoid model may serve as a relevant model for studying human lipopoprotein metabolism, including Lp(a).

中文翻译：

---

在 Biomimesys® 透明质酸水支架上生长的人类诱导多能干细胞衍生的肝脏类器官，作为研究人类脂蛋白代谢的新模型

肝脏在脂蛋白的代谢中起着关键作用，控制着脂蛋白的产生和分解代谢。为了加速人类新降脂疗法的开发，有必要拥有相关的体外研究模型。目前源自 hiPSC 的肝细胞样细胞 (HLC) 模型可用于模拟许多遗传驱动的疾病，但需要进一步改进以更好地概括肝功能的复杂性。在这里，我们的目标是使用 Biomimesys® 的三维 (3D) 方法来提高 HLC 的成熟度，Biomimesys® 是一种基于透明质酸的水支架，其中 hiPSC 可以直接形成聚集体并分化为功能性肝脏类器官模型。经过 28 天的分化 3D 方案后，我们发现与 2D 模型 (HLC) 相比，3D 模型（肝类器官）中许多肝脏基因上调。在 Biomimesys® 上生长的肝脏类器官表现出自主细胞组织，由不同的细胞类型组成，并且与 HLC 相比，细胞色素 P450 活性增强。关于这些类器官的功能，我们表明它们能够积累脂质（肝脂肪变性）、内化低密度脂蛋白并分泌载脂蛋白 B。有趣的是，我们首次表明该模型也能够产生载脂蛋白（ a)，Lp(a) 特异的载脂蛋白 (a)。这种创新的 hiPSC 衍生的肝脏类器官模型可以作为研究人类脂蛋白代谢（包括 Lp(a)）的相关模型。