Engineering multicellular systems: Using synthetic biology to control tissue self-organization

The control of multicellular systems in general and of tissue formation in particular is a frontier for regenerative medicine and basic biological research. Current manipulations of multicellular systems such as tissue engineering, in vitro organoid development, and stem cell differentiation are revolutionizing the field, yet remain confronted with difficulties controlling precision, complexity, and functional integration. New methodologies and tools are needed to address these issues before the ambitious goal of building complex, customizable organs and tissues can be achieved. One promising approach is starting to make gains in this area: the genetic engineering of cellular signaling to directly or indirectly affect cellular self-organization. This review will focus on genetic manipulations that make use of, and/or are modeled after, the self-organization programs that multicellular systems use during development and regeneration. In particular, current examples and future directions of the following three areas will be explored: (i) Engineering developmental trajectories in non-developmental systems, with an example for epithelial patterning; (ii) Engineering control in developmental systems, with an example of increasing cellular composition complexity in stem cell differentiation; (iii) Engineering regeneration in non-regenerating systems, with an example from limb regeneration with engineered cells. The use of synthetic biology to control the genetic layer of these three areas will undoubtedly uncover important rules dictating cellular self-organization, putting us one step closer to a powerful approach for building multicellular systems, one we will call synthetic tissue development. In the future, we anticipate that convergence of this approach with more established approaches to multicellular system control will lead to improved functional tissue formation in vitro and the possibility of transformative advances in regenerative medicine.