Cell functions, such as adhesion, migration, proliferation, differentiation, organization, protein expression and death, are dynamically regulated at the surface of cell membranes by the interaction between a ligand molecule of the cellular microenvironments and the membrane protein receptors. Furthermore, physical signals of cellular microenvironments, stiffness, elasticity and hydration, are also important factors for the modulation of cellular functions. In the body, natural extracellular matrices (ECMs) and ECM-bound growth factors regulate cell functions. The universal control of cell functions at the single-cell level through the artificial modulation of extracellular microenvironments by mimicking the natural ECMs would be a key technique for biomedical fields. In the present review, the fabrication of nanometer-sized artificial ECM films using various polymers and proteins on single-cell surfaces to control cell functions is described. The thickness, charge and component of the ECM films were observed to significantly affect the cell functions. Moreover, the optimized ECM films induced cell-cell organization to construct three-dimensional human tissue chips. Control of extracellular microenvironments using a nanometersized polymer/protein film as an artificial ECM would be useful as a novel technique to regulate cell functions as desired.
INTRODUCTIONTissue cells in the body reside in the micrometer-sized fibrous meshwork of the extracellular matrix (ECM). Tissue dynamics, such as formation, function and regeneration after damage, are the result of an intricate temporal and spatial coordination of numerous individual cell fate processes, each of which is induced by a myriad of signals originating from the extracellular microenvironment (Scheme 1). 1 The extracellular microenvironment is a hydrated protein and proteoglycan-based ECM gel network comprising soluble and physically bound signals as well as signals arising from cell-cell interactions. 2 The ECM is typically composed of fibronectin (FN), collagen and laminin and provides complex biochemical and physical signals. 3,4 The ECM not only stores growth factors and cytokines but also induces cell-cell contacts and cell-matrix interactions. 2 Accordingly, control of the cellular microenvironment using artificial ECM and growth factors will be an important in vitro technique to control cell growth, cytokine expression, stem cell differentiation and extracellular assembly. To control the cellular microenvironment, the patterning of substrate surfaces 5 and the chemical modifications of cell surfaces 6-8 have been generally used. However, substrate modification cannot modify the important cell apical membrane, and chemical modifications have limitations because of cytotoxicity, complicated methodology or less application.