Engineering Liver Tissue to Grow on Demand

In end-stage liver disease, the liver’s natural ability to regenerate is no longer enough to repair the damage, leaving transplant as the only treatment option. But because donor livers are scarce, many patients remain on transplant lists, and some become too sick to receive an organ in time. To address this challenge, a research team from the Wyss Institute at Harvard University, Boston University, and MIT developed a different strategy: implant a small liver construct and then encourage it to expand inside the body after engraftment.

The team combined tissue engineering and synthetic biology in a method they called BOOST, short for “bioengineered on-demand outgrowth via synthetic biology triggering.” By reprogramming primary liver hepatocytes and supportive fibroblast cells, they were able to activate a growth program in small engineered liver tissues after implantation into mice. Their work was published in Science Advances. 

To find the right signals for growth, the researchers screened candidate growth factors and identified four—HGF, TGFa, WNT2, and RSPO3—that strongly stimulated sparsely scattered human primary hepatocytes in culture. However, those same factors did not work in densely packed 3D liver tissues. That result led the team to investigate YAP, an intracellular protein involved in sensing mechanical signals and regulating proliferation. When they overexpressed a non-degradable form of YAP, the cells were able to override the normal density checkpoint, though growth in dense tissue still required both YAP and the growth factors.

The researchers then used synthetic biology tools to make the system controllable. They engineered fibroblasts to secrete the growth factors and hepatocytes to express non-degradable YAP, and they made all of these proteins inducible with doxycycline. In culture, seven days of doxycycline treatment led to robust tissue expansion, while removing the drug returned the cells to a non-proliferative state. The team also observed a trade-off: increased growth was associated with a less functional hepatocyte state.

When the engineered tissue was implanted into mice and the animals were treated with doxycycline for seven days, the tissue expanded further, showed a 500% increase in proliferation, doubled the number of engineered hepatocytes, and became vascularized. The implants were well tolerated, with no signs of fibrosis, immune-cell-driven inflammation, or tumor growth. The researchers noted that, unlike earlier approaches, their method did not require injury to the host liver to trigger engraftment and growth.

The team says this strategy could support future non-surgical control of solid organ cell therapies and may also be relevant to other engineered tissues that face scale-up challenges.