Project Description The goal of this NEW PROJECT is to engineer liver tissue grafts in which the timing and extent of graft vascularization and expansion in a living host is directly manipulable. In vivo, cell-to-cell communication mediated through paracrine signals is a hallmark of multicellular life, and in the liver is thought to play a critical role in driving tissue vascularization and growth. In collaborative studies, the investigators have recently established experimental models of liver tissue that incorporate hepatocytes, endothelial cells, and stromal cells spatially patterned to bolster these cell-cell interactions. These interactions enable vascularization regenerative expansion of engineered human liver tissue both in vitro, in a microfluidic human liver model, and in vivo, in an ectopically implanted human liver graft. In this proposal, the investigators will build upon these model systems by leveraging synthetic transcription factors to take control over the dynamics of paracrine signaling within the engineered livers to enable controlled, on-demand tissue vascularization and expansion. The specific aims of this new proposal are: (1) To build functional vasculature in engineered tissue through synthetic vascularization, (2) To establish on-demand expansion of engineered functional liver tissue through synthetic regeneration, and (3) To develop approaches for system integration and robustness in suboptimal host environments. Together, leveraging both in vitro and in vivo models, these efforts will endow precise control of function, expansion, and engraftment of engineered vasculature and hepatic parenchyma and will more generally establish a new approach for synthetic control of engineered tissues that will advance engineered organ grafts closer towards clinical utility.

Lay Summary The engineering of implantable tissues has the potential to address the shortage of organs available for transplantation; however, for solid organs like the liver, progress has been stymied by the lack of a robust blood supply to support key functional cells as well as the inability to harness the natural regenerative capacity of the liver to grow in the face of sudden injury. This project will develop new tools to control both the processes of blood vessel growth (vascularization) and tissue growth (expansion) by taking control over the cell-cell signaling processes that normally coordinate the process and potentially improve upon these natural processes. As such, these studies will address several major hurdles towards the engineering of tissues for treating diseases that are otherwise only cured by whole organ transplantation.