Surface tension drives neuronal sorting in magnetically engineered brain-like tissue

Engineered 3D brain-like models have advanced the understanding of neurological mechanisms and disease, yet their mechanical signature, while fundamental for brain function, remains understudied. The surface tension for instance controls brain development and is a marker of cell-cell interactions. Here, we engineered 3D magnetic brain-like tissue spheroids composed of intermixed primary glial and neuronal cells at different ratios. Remarkably, the two cell types self-assemble into a functional tissue, with the sorting of the neuronal cells towards the periphery of the spheroids, whereas the glial cells constitute the core. The magnetic fingerprint of the spheroids then allows their deformation when placed under a magnetic field gradient, at a force equivalent to a 70 g increased gravity at the spheroid level. The tissue surface tension and elasticity can be directly inferred from the resulting deformation, revealing a transitional dependence on the glia/neuron ratio, with the surface tension of neuronal tissue being much lower. This provides the underlying mechanical explanation for the exclusion of the neurons towards the outer spheroid region, and depicts the glia/neuron organization as a surface tension-driven sophisticated mechanism that should in turn influence brain development and homeostasis.