Growing human stem cells into functional 3D liver tissue

As liver diseases continue to increase in prevalence, there is a call for metabolically functional liver tissue for transplant. Scientists from the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh have been looking at human induced pluripotent stem cells (iPSCs) as a potential solution to the problem, and they've reported promising early results from an effort to grow the cells into functional liver tissue in mice.

In a study published in the journal Archives of Toxicology, the researchers used embryonic stem cells and iPSCs to develop hepatocytes and grew them in a dish for over a year. According to Professor David Hay, Ph.D., who led the study, this is the first time stem cell-derived liver cells have been kept alive in the lab for that long a time.

“Keeping the cells alive and stable as liver cells for a long time is a very difficult step, but crucial if we hope to use this technology in people,” he said in a statement.

To give the cells structure, the scientists tapped material chemists and engineers to build 3D scaffolds with polycaprolactone, a biodegradable polyester approved for use in humans. Liver cells were then loaded onto the scaffolds and implanted under the skin of mice to test their activity in a way that would be less invasive than implanting them into the abdomen.

They tested the tissue scaffolds in mice with tyrosinemia, a potentially fatal genetic disorder in which the liver’s enzymes fail to break down the amino acid tyrosine, leading to a toxic buildup of tyrosine and its byproducts. In the animals' blood, researchers found proteins synthesized by the liver, meaning that the tissue had integrated with the circulatory system.

The new tissue helped the mice break down tyrosine, and the animals lost less weight compared to others that received empty scaffolds. The treated mice also showed fewer signs of liver damage, the team reported.

“These results are an important early step and now we need to conduct longer-term studies to fully establish the safety of this technique and to scale up and optimize the performance of the liver tissue so we can move this technology towards clinical trials,” said Hay.

Because of a shortage of organ donors and other issues with transplants, scientists around the world are looking to cell therapy as a regenerative method to treat organ failure. A group of scientists in Japan demonstrated in a 2013 Nature study that iPSCs co-cultured with mesenchymal stem cells and endothelial cells can self-assemble to form in vitro a 3D liver “bud,” which shows some liver functions when transplanted into mice. In a 2015 study published in the journal Nature Cell Biology, another MRC team found that transplanted liver stem cells, or hepatic progenitor cells, helped mice recover from severely damaged livers.

Rather than growing tissues ex vivo, scientists at UC, San Francisco, are attempting to create tissues within the body, and they've made some early progress using a synthetic signaling molecule called synNotch. Ambys Medicines—a Third Rock Ventures company that recently emerged with a $100 million deal with Takeda—is working on cell therapy for hepatocyte transplantation and gene therapy for liver regeneration.

The MRC team working on the iPSC-derived liver scaffold hopes the technique could one day help people with failing livers. It might also aide drug discovery, both by providing a platform to study liver disease and a way to test new medicines, since many drugs are metabolized through the liver.