All-in-one rheology of multicellular aggregates

Abstract

Tissues are generally subjected to external stresses, a potential stimulus for their differentiation or remodelling. While single-cell rheology has been extensively studied, mechanical tissue behavior under external stress is still poorly known because of a lack of adapted set-ups. Herein we introduce magnetic techniques designed both to form aggregates of controlled size, shape and content (magnetic molding) and to deform them under controlled applied stresses over a wide range of timescales and amplitudes (magnetic rheometer). We explore the rheology of multicellular aggregates (F9 cells) using both standard assays (creep and oscillatory response) and an innovative broad spectrum solicitation coupled with inference analysis. We find that multicellular aggregates exhibit a power-law response with non-linearities leading to tissue stiffening at high stress. Comparing magnetic measurements on aggregates to isolated F9 cells characterization by parallel-plates rheometry, we reveal the role of cell-cell adhesions in tissue mechanics. Thanks to its versatility, the magnetic rheometer thus stands as an essential tool to investigate model tissue rheology.

A microfluidic platform to investigate the role of mechanical constraints on tissue reorganization

“…To study these in vitro tissue rheology in the context of developmental biology, several experimental setups have already been used, including cell monolayers stretching (3), rounding of cell aggregates (4–6), shearing of cell monolayers or cell aggregates (7–10), and compression of cell aggregates (5, 11, 12). These experiments have enabled to measure tissue bulk parameters such as shear and compression moduli, viscosity, surface tension and yield stress.…”

“…For example, cell monolayers can be stretched by being suspended between rods or on an elastic membrane while imaging the tissue response at the cellular level (15, 16). Nanometric magnetic beads naturally endocytosed by the cells have also been used to apply a global force on cellular aggregates (12, 17).…”