IN A MAJOR advance for human liver modeling, researchers have created pluripotent stem cell–derived fetal liver-like organoids (FLOs) that simultaneously develop hepatic tissue and a functional hematopoietic system. The platform replicates core features of fetal hemato-hepatogenesis and provides a long-sought human model for studying immune–liver interactions during development and disease.
Reconstituting the Fetal Liver Niche
To overcome the absence of an endogenous blood-forming microenvironment in existing liver organoid systems, investigators co-developed hemogenic mesoderm with hepatic endoderm. This produced FLOs containing hepatobiliary, endothelial, and mesenchymal tissues, alongside multipotent hematopoietic progenitor cells (HPCs) with dominant myeloid bias but preserved fetal B- and T-cell potential. Single-cell and bulk transcriptomics confirmed stepwise lineage maturation in the absence of exogenous differentiation cues.
CXCL12–CXCR4 Signaling Drives Hematopoietic Emergence
Within the FLO niche, researchers identified a key instructive circuit, CXCL12–CXCR4, that supports hematopoietic development in a manner consistent with in vivo fetal liver physiology. Supplementation with a small-molecule–cytokine cocktail allowed directed expansion of immune lineages, yielding granulocytes and polarized macrophages with appropriate effector functions.
Modeling Steatotic and Lipotoxic Injury
Functionally, FLO-derived immune cells mounted robust responses to inflammatory triggers. Notably, under steatotic–lipotoxic stress, FLOs recapitulated an IL-8–driven neutrophil injury cascade, providing a mechanistic window into how innate immune responses contribute to fatty-liver pathology.
Translational Significance
The authors argue that FLOs offer a scalable and physiologically aligned system for probing human fetal liver development, modeling pediatric liver diseases, and testing regenerative interventions. Because the platform yields immune-competent liver tissue, it may also advance drug screening and precision-medicine approaches for immune-mediated hepatic injury, including applications in gene-edited cell replacement, tolerance induction, and patient-specific toxicity profiling for drug candidates.
Reference
Rezvani M et al. Modeling Immune Lineage Co-Development in Human Pluripotent Stem Cell–Derived Liver Organoids. Cell Stem Cell. 2025;doi:10.1016/j.jhep.2025.11.018.
