CELLULAR AND MOLECULAR RESPONSES TO MECHANICAL CUES: FROM THE EXTRACELLULAR MATRIX TO THE NUCLEUS
- Author(s): Jahed Motlagh, Zeinab
- Advisor(s): Mofrad, Mohammad R.K.
- et al.
Mechanical signals affect virtually every fundamental single- and multi-cellular process in biology. The local responses of individual molecules to mechanical stimuli at the interface of cell with its adjacent microenvironment (extracellular matrix or material) elicit global responses at the cell and tissue scales. Understanding and manipulating the cell-material interaction can be leveraged to design biomaterials with unique characteristics tailored towards a wide variety of biological applications such as platforms that direct stem cell differentiation for tissue engineering, sensors that can record accurate electrical signals in single cells for neuroscience, and implants that are susceptible to cell adhesion for biomedical applications. In this thesis I present work characterizing the response of cells to mechanical stimuli at the single cell and single molecule scales. At the single cell scale, we provide insights into how mechanical signals such as micro- and nano-topography of metallic and metallic surfaces affect cell adhesion, both in mammalian and bacterial cells. Next we characterize the mechanical response of protein complexes involved in the transmission of mechanical signals across the cytoskeleton to the nucleus.
The four main contributions of the work presented in this thesis are as follows: 1) We used high resolution scanning electron microscopy to characterize the cell-nanostructure interface and provide insights into the response of individual mammalian cells to nanostructures with complex geometries. 2) We provide a first look at how individual bacterial cells adhere to metallic nanostructures, which could lead to new techniques to thwart infections. 3) We proposed a novel technique to control the growth and arrangements of bacterial cell communities. This method will allow precise small-scale mechanical manipulation of bacterial cells and could be utilized for unraveling the understudied mechanisms of bacterial mechanosensitivity. 4) We performed the first molecular dynamics study on the mechanisms of force transmission to the nucleus of eukaryotic cells through protein complexes known as linkers of the nucleoskeleton and cytoskeleton (LINC complexes). We showed that LINC complexes are highly stable under tensile forces, and that the transmission of force across the complex depends highly on the unique intermolecular covalent bonds formed between the two proteins that construct the complex. Finally, we presented a model for the molecular mechanisms of LINC complex activation and regulation at the nuclear envelope.