Synthetic control of angiocrine signaling in vascularized liver implants

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Massachusetts Institute of Technology $100,228 on May 1, 2027, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to develop and apply synthetic biology tools to engineer vascularized human liver tissues capable of dynamically responding to regenerative stimuli.

The project establishes closed-loop synthetic gene circuits regulating proangiogenic and hepatoprotective growth factors in vitro, then assesses how autonomous paracrine signaling directs new vascular networks and hepatic expansion in vivo. This work implements advances in microphysiological systems and mammalian synthetic biology to program cell-cell communication within multicellular tissues, providing an innovative toolkit for responsive control of tissue assembly and function. The long-term objective is to provide clinically relevant platforms for cell-based therapies to address liver failure, where transplantation is limited by donor organ scarcity.

Performance of research occurs at Cambridge, Massachusetts. The period of performance runs from May 1, 2027, through August 31, 2028.

Abstract

This project aims to develop and apply synthetic biology tools to engineer vascularized human liver tissues capable of dynamically responding to regenerative stimuli. The long-term objective is to provide clinically relevant platforms for cell-based therapies to address liver failure, where transplantation is limited by donor organ scarcity. The central hypothesis driving this research is that autonomous recapitulation of critical paracrine signaling found in a healthy, regenerating liver can enable tunable vascularization and hepatic expansion in engineered liver tissues. The specific aims are to: (1) establish closed-loop synthetic gene circuits regulating proangiogenic and hepatoprotective growth factors in vitro and (2) assess how autonomous paracrine signaling directs new vascular networks and hepatic expansion in vivo. The proposed work implements advances in microphysiological systems in tissue engineering and mammalian synthetic biology to interrogate and program cell-cell communication within multicellular tissues, providing an innovative toolkit for responsive control of tissue assembly and function. By advancing strategies for the precise modulation of multicellular dynamics to engineer vascularized, regenerating tissues, this work can be extended to establish new frameworks for adaptive and self-regulated cell therapies for organ support and repair. This project leverages emerging synthetic biology and bioengineering platforms to transform our ability to construct and regulate complex human tissues, enhancing understanding and treatment of liver failure. Research will be conducted at an interdisciplinary training environment with easy access to state- of-the-art imaging capabilities and animal facilities and with an established, collaborative team integrating expertise in vascular biology, liver biology, microphysiological systems, and synthetic biological control systems.