Synthetic Control of Implanted Engineered Liver Tissue Growth

Abstract Despite the promise of engineered tissue implants for the treatment of organ failure, scaling of these constructs to sizes of therapeutic relevance remains a barrier to clinical translation. Here, we propose a strategy to circumvent this limitation: to instead implant a small-scale construct and then induce it to grow in situ after its engraftment into a host. Using engineered liver tissue as a proof-of-concept application, we integrated synthetic biology and tissue engineering tools to build liver tissues that can be expanded on-demand after implantation in vivo. To achieve this goal, we first identified the combination of YAP and growth factor signaling as sufficient to drive human hepatocyte proliferation in dense, 3D engineered tissues. We then engineered control of these signaling axes using synthetic biology tools to drive human liver tissue expansion both in vitro and in vivo. As such, this work establishes a genetic strategy for generating large organ implants through bioengineered, on-demand outgrowth using synthetic triggers (BOOST). Teaser Presenting bioengineered on-demand outgrowth via synthetic biology triggering (BOOST) for in situ solid cell therapy scale up. Competing Interest Statement SNB reports interests in Sunbird Bio, Satellite Bio, Catalio Capital, Port Therapeutics, Matrisome Bio, Xilio Therapeutics, Ochre Bio, Vertex Pharmaceuticals, Moderna, Johnson & Johnson, and Owlstone. SNBs interests are reviewed and managed under MITs policies for potential conflicts of interest. CSC is a founder and owns shares in Innolign Biomedical, Satellite Biosciences, and Ropirio Therpuetics. None of these companies were involved with this study. All other authors declare that they have no competing interests. Footnotes Figure versions, supplemental captions, and funding sources updated