Abstract：
Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.
摘要：
最大限度地发挥人类肝脏类器官（LOs）的潜力，以模拟人类败血症肝脏需要先天免疫细胞的整合，特别是常驻巨噬细胞Kupffer细胞。在这项研究中,我们提出了一种策略，通过使用人类诱导的多能干细胞（hiPSC）衍生的红骨髓祖细胞（EMPs）来概括胎儿肝脏造血，从而产生含有Kupffer细胞（KuLOs）的LOs，组织驻留的巨噬细胞的起源，和hiPSC派生的LOS。值得注意的是,LOs积极促进EMP造血向骨髓和红系谱系。此外，在KuLOs建立过程中，补充巨噬细胞集落刺激因子（M-CSF）对于维持造血种群至关重要。将KuLOs暴露于败血症样内毒素会导致明显的类器官功能障碍，这与人类败血症肝脏的病理特征非常相似。此外，我们观察到内毒素消除后KuLOs的显着功能恢复，通过使用针对Toll样受体4的内毒素拮抗剂加速。我们的研究代表了将造血细胞整合到类器官中的综合框架，促进对炎症介导的肝脏病理的深入研究。
