From natural to synthetic hydrogels: how much biochemical complexity is required for mechanotransduction?

The biochemical complexity of a material determines the biological response of cells triggered by a cell-material interaction. The degree in which this complexity influences basic cell-material interactions such as cell adhesion, spreading, and mechanotransduction is not entirely clear. To this end, we compared three different hydrogel systems, ranging from completely natural to synthetic, in their ability to induce mechanotransduction in kidney epithelial cells (HK-2). A natural hydrogel system was developed based on a decellularized kidney extracellular matrix (dECM). Supramolecular ureido-pyrimidinone (UPy)-glycinamide molecules, with self-associative behavior, were used for a hybrid and complete synthetic system. A hybrid system was engineered by co-assembling this monovalent UPy molecule with a hyaluronic acid, functionalized with ∼7 UPy-groups (UPy-HA), into a transient network. A similar approach was used for the synthetic hydrogel system, in which the multivalent UPy-HA was replaced with a bivalent UPy-PEG molecule with bioinert properties. Both hybrid and synthetic hydrogel systems were more mechanically tunable compared to the dECM hydrogel. The higher bulk stiffness in combination with the introduction of collagen type I mimicking UPy-additives allowed these materials to induce more nuclear yes-associated protein translocation in HK-2 cells compared to the biochemically complex dECM hydrogel. This demonstrated that minimal biochemical complexity is sufficient for inducing mechanotransduction.