Programming multicellular assembly with synthetic cell adhesion molecules

Abstract

Cell adhesion molecules are ubiquitous in multicellular organisms, specifying precise cell–cell interactions in processes as diverse as tissue development, immune cell trafficking and the wiring of the nervous system1–4. Here we show that a wide array of synthetic cell adhesion molecules can be generated by combining orthogonal extracellular interactions with intracellular domains from native adhesion molecules, such as cadherins and integrins. The resulting molecules yield customized cell–cell interactions with adhesion properties that are similar to native interactions. The identity of the intracellular domain of the synthetic cell adhesion molecules specifies interface morphology and mechanics, whereas diverse homotypic or heterotypic extracellular interaction domains independently specify the connectivity between cells. This toolkit of orthogonal adhesion molecules enables the rationally programmed assembly of multicellular architectures, as well as systematic remodelling of native tissues. The modularity of synthetic cell adhesion molecules provides fundamental insights into how distinct classes of cell–cell interfaces may have evolved. Overall, these tools offer powerful abilities for cell and tissue engineering and for systematically studying multicellular organization.

Bioorthogonal photocatalytic quinone methide decaging for cell-cell interaction labeling

“…The sensitivity and selectivity of the labeling method were demonstrated in the TCR-pMHC system and the broad utility was proven by detection of multiple cell types (including HEK293T, antigen-specific T cells and NK cells). By rational design and establishment of quinone methide probes and platforms, we provided a photocatalytic decaging method differing from those doublet-based methods requiring external computational assistant 41 or contact-dependent methods which may have concerns due to the artificial cellular interaction interference 42,43 . It is also complementary to the proximity labeling methods based on specific enzyme or chemical intermediates for intercellular interaction labeling.…”

Open-endedness in synthetic biology: a route to continual innovation for biological design

“…In biological systems, the evolution of multi-cellularity [147] is a prime example of such a higher-level entity. The artificial transition to multicellularity has been realized in several experiments [73,22], while platforms like synNotch [145] and synCAM [142] have been used to let cells self-assemble into complex multicellular structures. Cells can also be assembled in a top-down fashion into completely new organisms with programmed behaviour [81,16].…”

Coiled Coils as Versatile Modules for Mammalian Cell Regulation

“…By expressing orthogonal coiled coil forming polypeptides fused to a transmembrane domain on a mammalian cell surface, they constructed three-dimensional cell structures and managed to specifically target suspension cells to adherent cells. Stevens et al [45] systematically explored the modularity of CAMs. They prepared several synthetic CAMs (synCAMs) by fusing orthogonal extracellular binding domains (ECD) to endogenous CAM intracellular domains from native adhesion molecules (Figure 4b).…”