Synthetic Biology Approach Enables On-Demand Liver Tissue Growth

Access to donor livers remains limited, with thousands on waiting lists and many patients deteriorating before surgery. The inability to scale engineered liver tissue to therapeutic sizes further constrains care. To help address this challenge, researchers have developed a way to trigger growth of implanted liver constructs directly inside the body.

The Wyss Institute for Biologically Inspired Engineering at Harvard University, with Boston University and the Massachusetts Institute of Technology, developed a genetic strategy called bioengineered on-demand outgrowth via synthetic biology triggering (BOOST). The approach is designed to establish a “satellite liver” by implanting a small engineered construct and then expanding it in vivo as needed. The goal is to offload metabolic demand from a failing liver and potentially bridge patients to transplant.

To enable controlled in situ growth, the team first identified the signals needed to stimulate human hepatocyte expansion. Because liver growth is regulated by soluble growth factors, the researchers screened candidate molecules in cultured primary human hepatocytes. They identified four factors—HGF, TGFα, WNT2, and RSPO3—that strongly promoted growth in cells spread out in culture. However, these factors alone were not effective in densely packed liver tissues containing hepatocytes and fibroblasts, suggesting that an additional mechanism limits growth under these conditions.

The team then investigated the protein YAP, which helps regulate cell growth in response to mechanical signals. In less crowded environments, YAP moves into the nucleus and activates genes linked to proliferation, while in tightly packed tissues it is broken down, preventing this response. By engineering hepatocytes to produce a stable form of YAP, the researchers were able to bypass this density-related limit. They found that both YAP activation and growth factor signals were needed together to drive expansion in three-dimensional liver constructs.

BOOST brings these elements together by combining tissue engineering with synthetic biology to locally control these signaling pathways within the implanted tissue. Fibroblasts were engineered into separate cell lines, each programmed to secrete one of the four growth factors, while hepatocytes were modified to express the stabilized YAP variant. All components were placed under a doxycycline-inducible system, meaning the growth program is activated only in the presence of the commonly used and harmless antibiotic doxycycline, switching off once it is withdrawn.

In culture, a continuous seven-day doxycycline regimen increased the size and cell number of engineered liver tissue, with cells returning to a resting state once the drug was removed. Time-course experiments confirmed that this expansion could be precisely controlled, enabling growth to be turned on and off as needed. Single-cell analyses showed that faster growth was accompanied by a temporary reduction in hepatocyte function, reflecting a broader biological trade-off between proliferation and function that the team aims to refine in future work.

After implantation in mice, induced tissues showed a 500% increase in proliferation, a doubling of engineered hepatocytes, and sufficient blood vessel formation to support metabolic activity. The expanded tissues were well tolerated, with no evidence of fibrosis, inflammation, or tumor formation, and growth did not require injury to the host liver.

The findings, published in Science Advances on April 17, 2026, lay the groundwork for non-surgical control of solid organ cell therapies. The team plans to evaluate whether BOOST-expanded liver tissue can restore function in models of liver injury and suggests that similar approaches could support scaling of engineered cardiac or pancreatic tissues.

“Our BOOST strategy lays the foundation for a future when solid organ cell therapies can be controlled non-surgically according to the needs of patients and their physicians. Beyond treating liver disease, the premise of BOOST could be applied to other engineered tissue therapeutics that are similarly constrained by challenges associated with tissue scale-up, such as engineered heart or pancreatic tissue to address serious diseases,” said Sangeeta Bhatia, M.D., Ph.D., Associate Faculty member at the Wyss Institute, John J. and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT, and a Howard Hughes Medical Institute Investigator.

Related Links
Wyss Institute for Biologically Inspired Engineering at Harvard University