Abstract
Building tissue from cells as the basic building block based on principles of self-assembly is a challenging and promising approach. Understanding how far principles of self-assembly and self-sorting known for colloidal particles apply to cells remains unanswered. In this study, we demonstrate that not just controlling the cell–cell interactions but also their dynamics is a crucial factor that determines the formed multicellular structure, using photoswitchable interactions between cells that are activated with blue light and reverse in the dark. Tuning dynamics of the cell–cell interactions by pulsed light activation results in multicellular architectures with different sizes and shapes. When the interactions between cells are dynamic, compact and round multicellular clusters under thermodynamic control form, while otherwise branched and loose aggregates under kinetic control assemble. These structures parallel what is known for colloidal assemblies under reaction- and diffusion-limited cluster aggregation, respectively. Similarly, dynamic interactions between cells are essential for cells to self-sort into distinct groups. Using four different cell types, which expressed two orthogonal cell–cell interaction pairs, the cells sorted into two separate assemblies. Bringing concepts of colloidal self-assembly to bottom-up tissue engineering provides a new theoretical framework and will help in the design of more predictable tissue-like structures.
Highlights
The bottom-up assembly of a spatially ordered tissue made from cellular building blocks based on the principles of self-assembly is a highly promising and powerful approach to tissue engineering and an extreme synthetic and biological challenge at the same time.[1]
Going forward, it is indispensable to understand how cells as the basic building blocks of tissue self-assembly. This requires controlling the interactions between cellular building blocks and understanding to what extent the principles of selfassembly and self-sorting known for nonliving colloidal particles apply to cells.[9]
While compact and spherical structures at the thermodynamic equilibrium form under reaction-limited cluster aggregation (RLCA), loose and ramified assemblies in kinetically trapped states form under diffusion-limited cluster aggregation (DLCA).[12−14] This puts forward the importance of not just controlling the interactions between the colloidal/ cellular building blocks and their dynamics
Summary
Letter interactions have been controlled by modifying the surfaces of cells with complementary DNA strands,[15] biotin−streptavidin,[16] clickable functional groups,[17,18] supramolecular interaction partners,[18,19] and the photoswitchable protein pair CRY2/CIBN.[20]. NMagHigh, and pMagHigh were not combined as these proteins bind to one another.[32] In both of the four-component mixtures, we observed higher light-dependent aggregation under continuous blue light illumination than in the dark overnight (Figure 3b,d,e, Supporting Information, Figure S8), yet the aggregates differed in the organization of the different cell types. In the former mixture, iLID- and Nano-MDA cells (stained in red) clustered separately from the nMag- and pMag-MDA cells (stained in green), showing social sorting of the four cell types (Figure 3b). Experimental methods, characterization of the cell lines, images used for analysis, control experiments, and additional examples (PDF)
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