Periodic Reporting for period 1 - MECHANOSITY (Mechanical regulation of cellular behaviour in 3D viscoelastic materials)
Período documentado: 2019-09-01 hasta 2021-08-31
Extracellular matrix (ECM) mechanical properties have emerged as key promoters of processes such as cell migration and epithelial to mesenchymal transition (EMT) in cancer. Despite recent advances in the understanding of cellular ECM sensing machinery, mimicking tissue microenvironments in vitro is highly challenging, and most research has been focused on two dimensional (2D) elastic substrates. However, ECMs are not merely 2D elastic substrates, but rather viscoelastic three-dimensional (3D) materials. All our tissues and organs in our bodies are viscoelastic, behave both as solids and as liquids. Our objective is to understand how the viscoelastic properties of 3D ECMs regulate tissue behaviour. Most research has focused only on the influence of elasticity as the main mechanical property that regulates tissue response. However, little importance has been drawn towards viscoelasticity. The ECM is not merely elastic but is instead both viscous and elastic. Due to its viscoelastic nature, the ECM response is time dependent and highly dynamic and how viscoelasticity affects tissue behaviour is unknown. This project has defined novel mechanonsensing mechanisms that regulate tissue response in in vivo like matrices that had not previously been observed. These mechanisms, due to the inherent viscoelastic nature of tissues, affect many biological fields from morphogenesis to cancer and more translational fields like biomaterials development or tissue engineering. We hypothesized that the viscoelastic nature of tissue was a more determinant mechanical property than stiffness in tissue response due to its dynamic nature and potential adaptability. To address the influence of viscoelasticity, Alberto Elosegui-Artola (the experienced researcher/ Applicant) will develop a set of hydrogels matching the viscoelastic properties of both healthy and malignant breast tissue. With these ideal system Alberto Elosegui-Artola has observed that matrix viscoelasticity regulates mammary epithelial cells migration and proliferation. This project’s results have revealed novel molecular mechanisms that could lead to new therapeutic targets in breast cancer, and also to provide translational opportunities in other disciplines including biomaterials and regenerative medicine.
The role of viscoelasticity has been studied thanks to the development of a novel hydrogel system where the viscoelasticity could be controlled independently of other properties, including stiffness, ligand density or pore size. These matrices have been chemically and mechanically characterized using several different techniques. Once these matrices were developed, the role of viscoelasticity in mammary epithelial cells behaviour was studied. The influence of matrix viscoelasticity in MCF10A cells with custom developed software. The main result is that viscoelasticity favours mechanotransduction and cell migratory and proliferative capacity. If the matrix viscoelasticity increases, cells divide and migrate faster.
This project has highlighted the role of breast epithelial cells. It is the first work that not only studies the role of viscoelasticity in single cells response, but also in tissues. As this project, shows that viscoelasticity is determinant in tissue malignancy, could have a great impact in the cancer field.