Non-viral gene delivery regulated by stiffness of cell adhesion substrates

Abstract

Non-viral gene vectors are commonly used for gene therapy owing to safety concerns with viral vectors. However, non-viral vectors are plagued by low levels of gene transfection and cellular expression. Current efforts to improve the efficiency of non-viral gene delivery are focused on manipulations of the delivery vector, whereas the influence of the cellular environment in DNA uptake is often ignored. The mechanical properties (for example, rigidity) of the substrate to which a cell adheres have been found to mediate many aspects of cell function including proliferation, migration and differentiation, and this suggests that the mechanics of the adhesion substrate may regulate a cell's ability to uptake exogeneous signalling molecules. In this report, we present a critical role for the rigidity of the cell adhesion substrate on the level of gene transfer and expression. The mechanism relates to material control over cell proliferation, and was investigated using a fluorescent resonance energy transfer (FRET) technique. This study provides a new material-based control point for non-viral gene therapy.

The effect of the alignment of electrospun fibrous scaffolds on Schwann cell maturation

“…Functional changes corresponding to changes in cell morphology can range from apoptosis to proliferation, differentiation, contractility, rate of cell migration, and gene expression. [24][25][26][27]. The cellular response and sensitivity towards growth factors and mitogens may also be altered.…”

Matrices and scaffolds for DNA delivery in tissue engineering

“…Matrix elasticity influences a range of cellular processes, such as contractility, migration, differentiation, and potentially organogenesis [45,131], and gene delivery has been investigated as a function of this elasticity [132]. Cellular internalization of polyplexes and increased polyplex dissociation was observed on hydrogels with greater rigidity, as increasing the matrix elastic modulus (E) of alginate from 20 to 110 kPa increased transgene expression for 400%.…”

Regenerative medicine in orthopaedic surgery

“…The mechanical properties of synthetic ECM, for example, will regulate the ability of cells to rearrange adhesion peptides presented from the material, 52 and through their control of cell proliferation will regulate transfection of adherent cell populations. 67 Externally applied mechanical signals will also regulate the response of cells to the synthetic ECM 68 and the release of growth factors and subsequent tissue formation. 69 …”