Tissue function derives from cooperation among a variety of specialized cell types, arranged into specific three dimensional structures, and embedded in a chemically defined extracellular matrix. Drawing mechanistic connections between the structure of a tissue and its function has been hampered by the inability to perturb tissue structure and measure the resulting tissue behavior in a systematic way. To address this challenge, we have developed a suite of chemical tools that allow for the reconstruction of precise three dimensional tissue geometries in the laboratory using purified human cellular building blocks. We use synthetic oligonucleotides grafted onto cell surfaces as temporary adhesion molecules that program the self-assembly of cell populations. Tissue assembly occurs through multiple synthetic steps beginning with a DNA patterned surface as a template. Assembly into the third dimension is directly analogous to multi-step solid-phase organic synthesis, and culminates in the cleavage of the completed tissue from the support and its release into hydrogels for 3D culture. Each cell in the completed tissue is placed with 10 �m precision and the overall structure can be up to 500 �m thick and span over 1 cm2. We apply this technique to assemble a properly structured human mammary epithelium, vasculature, and to dissect a mechanical and chemical signaling circuit that affects the invasion of Ras-transformed mammary epithelial cells toward neighboring fibroblasts in collagenous matrices.

Chemically programmed assembly of multiscale and multicomponent 3D human tissues with single cell resolution

246th National Meeting (2013)

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