The Frith Lab is focussed on understanding how cues from the extracellular environment direct stem cell fate (i.e. growth, motility and differentiation). We then aim to use this information to improve the design of cell-biomaterial composites for tissue engineering. Our work primarily uses mesenchymal stem cells (MSCs) which have great potential for musculoskeletal applications, for example getting the stem cells to create new bone to repair a particularly bad leg break or to regenerate cartilage to soothe worn-out knees or the degraded intervertebral discs that cause chronic back pain for so many people.
MSCs are highly sensitive to cues from their surrounding microenvironment. This includes factors such as substrate stiffness, time-dependent deformation, topography and ligand presentation. If we are able to understand how these signals are interpreted by the cell, and in turn how this leads to different cell states (a process called mechanotransduction), then there is a great opportunity to better design biomaterials to direct the activity of MSCs for different applications. For example, to force the cells to generate bone or cartilage, rather than adipose tissue. An understanding of the signalling events involved in mechanotransduction could also lead to new ways to direct MSC fate- for example by artificially up/downregulating a specific signalling pathway to over-ride information from the extracellular microenvironment.
For our research, we combine MSCs with 2D and 3D biomaterials, each with a specific set of physical and chemical properties. We then use a variety of cell biology techniques in order to understand what the cell is doing and what the mechanisms behind this are. This combination of the best in both biomaterials and biological techniques provides exciting new opportunities to understand and modulate cell activity.
We are investigating the signalling mechanisms that determine MSC fate in response to physical cues. Our research is currently investigating how microRNA signalling and epigenetic modifications (DNA methylation, histone modification) are involved in regulating the differences we see in MSC properties when cultured on soft or stiff substrates, as well as the key signalling pathways that these mechanisms target.
Hydrogels for MSC fate and delivery
Hydrogels provide an environment that is highly biocompatible- they are highly hydrated, allow for good diffusion of oxygen and nutrients, can be made using a variety of chemistries with tunable mechanical properties and have the potential to be injected into the body. We are interested in using hydrogels for MSC delivery into the body, whilst incorporating factors that can help to drive the cells to differentiate into the desired tissue type. We are particularly interested in optimising the delivery of factors (for example miRNAs) directly from the hydrogel to the cells inside to promote these processes.
Engineering MSC paracrine activities
Although the ability of MSCs to differentiate into bone, cartilage and adipose tissue makes them attractive candidates for tissue engineering, MSCs are also well-known for their paracrine activity, with MSC-secreted factors showing a great ability to both reduce inflammation and promote tissue regeneration. We are investigating how the extracellular microenvironment influences the secretion of such factors, to determine the optimal conditions for the production of pro-regenerative factors.