Tissue engineers heve demonstrate the ability to implant a seed consisting of a scaffold and liver cells into mice, and have it expand considerably into new tissue resembling natural liver tissue. This is an interesting hybrid approach between the two distinct strategies of growing tissue outside the body for transplantation and steering cell behavior to produce regrowth inside the body. Given the wide variety of technical initiatives aimed at organ regrowth, most of which are just as promising, it is hard to say at this point which of them will first break through into widespread use in human medicine.
Engineering human livers is a lofty goal. Human liver cells, hepatocytes, are particularly difficult to grow in the laboratory as they lose liver functions quickly in a dish. Now, researchers show that a “seed” of human hepatocytes and supporting cells assembled and patterned within a scaffold can grow out to 50 times its original size when implanted into mice. These engineered livers, which begin to resemble the natural structure of the organ, offer an approach to study organ development and as a potential strategy for organ engineering. “When we implant these tissues into a mouse with liver injury, the tissue seeds just blossom. Nature takes over and self-assembles a structure that looks like a human liver and has many liver-associated functions.”
In 2011, the researchers showed that human liver-cell aggregates could be grown in mice. They assembled human hepatocytes and supportive stromal cells within a polymer scaffold, demonstrating that this dime-size artificial human liver tissue could grow stably for weeks in immune-compromised mice that had their own normal livers. The liver implant fused with the mouse circulatory system and received blood to perform a few liver functions. In the new work, the lab wanted to expand the size of the human liver graft beyond the 1 million cells used in the prior model. The team assembled different geometries of human primary hepatocytes, human umbilical vein endothelial cells, and fibroblasts, placed them within a degradable hydrogel, and implanted the tissue seed into a fat pad within a liver-injury mouse model.
To recapitulate liver damage, the animals are missing a key amino acid metabolism gene that results in toxic metabolite build up and progressive liver failure, which can be rescued by a drug used to treat individuals with a similar genetic disorder. The group chose this model because it they expected it to foster the liver seeds’ growth. “The hypothesis is that mouse liver injury will produce factors that will travel through the blood stream and tell the human liver tissue to regenerate.” The team found that the human liver tissue grew less in animals that were continuously treated with the drug compared to animals that were given intermittent cycles of the drug.
The human liver seed tissue grew best when they assembled endothelial cells into rope-like structures on top of the hepatocytes, rather than when the tissue was a spherical aggregate of all three cell types. The patterned tissue formed new structures in vivo, including ones that resembled bile ducts, and contained pockets of red blood cells, suggesting the presence of vascular structures within the tissue. The organ-like structures also produced appropriate human proteins such as albumin and transferrin.