What do cells regulate in soft tissues on short time scales?

Cells within living soft biological tissues seem to promote the maintenance of a mechanical state within a defined range near a so-called set-point. This mechanobiological process is often referred to as mechanical homeostasis. During this process, cells interact with the fibers of the surrounding extracellular matrix (ECM). It remains poorly understood, however, what individual cells actually regulate during these interactions, and how these micromechanical regulations are translated to the tissue-level to lead to what we observe as biomaterial properties. Herein, we examine this question by a combination of experiments, theoretical analysis, and computational modeling. We demonstrate that on short time scales (hours) - during which deposition and degradation of ECM fibers can largely be neglected - cells appear to not regulate the stress / strain in the ECM or their own shape, but rather only the contractile forces that they exert on the surrounding ECM. STATEMENT OF SIGNIFICANCE: Cells in soft biological tissues sense and regulate the mechanical state of the extracellular matrix to ensure structural integrity and functionality. This so-called mechanical homeostasis plays an important role in the natural history of various diseases such as aneurysms in the cardiovascular system or cancer. Yet, it remains poorly understood to date which target quantity cells regulate on the mircroscale and how it translates to the macroscale. In this paper, we combine experiments, computer simulations, and theoretical analysis to compare different hypotheses about this target quantity. This allows us to identify a likely candidate for it at least on short time scales and in the simplified environment of tissue equivalents.