{Reference Type}: Journal Article
{Title}: Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis.
{Author}: Li Y;Nie Y;Yang X;Liu Y;Deng X;Hayashi Y;Plummer R;Li Q;Luo N;Kasai T;Okumura T;Kamishibahara Y;Komoto T;Ohkuma T;Okamoto S;Isobe Y;Yamaguchi K;Furukawa Y;Taniguchi H;
{Journal}: Cell Rep
{Volume}: 43
{Issue}: 3
{Year}: 2024 Mar 26
暂无{DOI}: 10.1016/j.celrep.2024.113918
{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.