Integration of Kupffer Cells into Human iPSC-Derived Liver Organoids for Modeling Liver Dysfunction in Sepsis

The study focuses on enhancing the potential of human liver organoids (LOs) for modeling septic liver conditions by integrating innate immune cells, specifically resident macrophage Kupffer cells. The researchers developed a strategy to generate LOs containing Kupffer cells (KuLOs) by mimicking fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), which give rise to tissue-resident macrophages, along with hiPSC-derived LOs.

Remarkably, these LOs actively promote EMP hematopoiesis towards myeloid and erythroid lineages. The addition of macrophage colony-stimulating factor (M-CSF) is crucial for sustaining the hematopoietic population during KuLO establishment. When exposed to sepsis-like endotoxins, KuLOs exhibit significant dysfunction resembling the pathological characteristics of human septic livers. However, the study also observes notable functional recovery in KuLOs upon endotoxin elimination, accelerated by using a Toll-like receptor-4-directed endotoxin antagonist. Overall, the research provides a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.