Directing tissue morphogenesis via self-assembly of vascular mesenchymal cells

Rebuilding injured tissue for regenerative medicine requires technologies to reproduce tissue/biomaterials mimicking the natural morphology. To reconstitute the tissue pattern, current approaches include using scaffolds with specific structure to plate cells, guiding cell spreading, or directly moving cells to desired locations. However, the structural complexity is limited. Also, the artificially-defined patterns are usually disorganized by cellular self-organization in the subsequent tissue development, such as cell migration and cell-cell communication. Here, by working in concert with cellular self-organization rather than against it, we experimentally and mathematically demonstrate a method which directs self-organizing vascular mesenchymal cells (VMCs) to assemble into desired multicellular patterns. Incorporating the inherent chirality of VMCs revealed by interfacing with microengineered substrates and VMCs' spontaneous aggregation, differences in distribution of initial cell plating can be amplified into the formation of striking radial structures or concentric rings, mimicking the cross-sectional structure of liver lobules or osteons, respectively. Furthermore, when co-cultured with VMCs, non-pattern-forming endothelial cells (ECs) tracked along the VMCs and formed a coherent radial or ring pattern in a coordinated manner, indicating that this method is applicable to heterotypical cell organization.