Lab-grown liver fragments with vascular lining and the growth protein IGF2 reduced fibrosis in mice
Lab-grown liver fragments with vascular lining and the growth protein IGF2 reduced fibrosis in mice
On August 7, in a Science Advances paper, Da-Hyun Kim’s team assembled organoids, which are lab-grown fragments of liver tissue, from human iPSC-derived cells. iPSCs are reprogrammed cells that can give rise to different tissue types. In this study, the researchers used them to produce liver cell precursors and the cells that line the inside of blood vessels.
The liver functions because different cells perform distinct tasks in the appropriate locations. Hepatocytes, the main cells of the liver, process substances in the blood. The endothelium, a thin layer of cells lining the inner surface of blood vessels, separates the blood from the surrounding tissue. The authors defined the engineering challenge as follows:
“Reconstructing a functional vascular network remains one of the main barriers to clinical application.”
The team removed the cells from a rat liver, leaving behind a protein scaffold that retained the existing geometry of the blood vessels. They seeded this scaffold with liver cell precursors and endothelial cells derived from the same human iPSC line. As a review explains, the vascular channels in such a scaffold must be lined with endothelial cells before they come into contact with blood. Otherwise, the exposed protein matrix can trigger clotting and obstruct blood flow. The researchers coated the channel walls with an anti-CD31 aptamer, a short molecule that binds to the CD31 protein on endothelial cells and helps the cells attach. In organoids with this coating, the endothelial cells formed a continuous lining, and a dextran dye remained inside the channels.
Spatial RNA analysis, which shows which genes are active in different regions of a tissue, identified IGF2, a growth signaling protein. When the researchers suppressed IGF2 in endothelial and liver cells grown separately, fewer cells survived, and the surviving cells developed fewer mature features of their respective cell types. The researchers tested four organoid variants with different combinations of vascular lining and IGF2. Adding laboratory-produced IGF2 during maturation, together with the vascular lining, produced the best measures of tissue structure and function.
In the transplantation experiment, the researchers damaged the mice’s livers with thioacetamide for eight weeks. They then transplanted the organoids and continued the injury treatment for another four weeks. Each group contained three mice in the key comparisons. Mice that received organoids with a vascular lining and IGF2 had less fibrosis, meaning less accumulation of scar tissue. They also had lower levels of ALT and AST, blood enzymes that rise when the liver is damaged.