A research team from the Wyss Institute at Harvard University, Boston University, and MIT announced on Apr. 17 a new synthetic biology strategy that could enhance the growth of implanted liver tissue. The method aims to help patients with end-stage liver disease by providing an alternative to full organ transplants, which are in short supply.
The shortage of donor livers means many patients either become too sick for surgery or die while waiting for a transplant. The researchers said their approach could relieve some pressure on the transplant system by enabling smaller engineered liver constructs to grow after implantation.
Christopher Chen, M.D., Ph.D., Core Faculty member at the Wyss Institute and Director of the Biological Design Center at Boston University, said: "We asked if it would be possible to first implant a small-scale liver construct and then drive it to expand in the body following its engraftment. A sufficiently grown, functional 'satellite liver' could immediately relieve the metabolic burden in a damaged liver and help bridge the time until a transplant becomes available." Chen described this project as an extension of ongoing collaborations with Sangeeta Bhatia, M.D., Ph.D., combining expertise in nanotechnologies and cellular engineering.
The team developed a genetic strategy called "bioengineered on-demand outgrowth via synthetic biology triggering," or BOOST. Amy Stoddard, Ph.D., who led much of this work during her doctoral research at MIT and as a postdoctoral fellow, explained that re-wiring gene expression allowed them to activate tissue growth programs in small engineered livers after implantation into mice. According to Stoddard: "We ended up with a set of four growth factors...that potently induced sparsely scattered HEPs to grow in the culture dish. But when we tested whether they could do the same in 3D liver tissues consisting of densely packed HEPs and fibroblasts, they turned out to be ineffective." This led them to investigate additional mechanisms regulating cell proliferation under high-density conditions.
Their findings showed that over-expressing a non-degradable version of YAP protein enabled cell proliferation even when cells were densely packed—a situation more similar to real tissue than traditional cell cultures. Using synthetic biology tools, they made protein expression inducible by doxycycline (DOX), allowing precise control over when tissue expansion occurs both inside laboratory dishes and living mice.
After seven days of DOX treatment post-implantation into mice, engineered tissues expanded significantly without causing adverse effects such as fibrosis or tumor formation. Stoddard said: "These results were particularly exciting...prior to our work, injury to the host liver has always been required to trigger hepatocyte engraftment and proliferation. Here we were able to relieve this dependence...in a completely healthy host." The team plans further studies exploring whether BOOSTed tissues can support hosts experiencing actual liver injury.
Bhatia added: "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." Donald Ingber, M.D., Ph.D., Founding Director at Wyss Institute said: "This collaborative study borne out of unique expertise...have led to an entirely new solution for liver that may equally valuable for confronting other diseases...demonstrates how we work at the Wyss Institute toward changing lives of patients who are often out of other options."
