The World Biomaterials Congress (WBC), which takes place once every four years, happened last month. Among the many excellent presentations at WBC, two themes related to cell-based therapies stood out: 1) the use of biomaterials to study cell behaviour and differentiation in vitro, which I will discuss here, and 2) the use of biomaterials to deliver cells or molecules to influence cells in vivo, which will be covered in a separate post.
Prof. Fiona Watt, the director of the Centre for Stem Cells and Regenerative Medicine at King’s College London, opened the conference with an excellent talk centred on interfollicular epidermal stem cell differentiation, and how interactions in this niche can be studied at the single cell level. Part of what helps a stem cell decide whether or not to remain a stem cell or to differentiate are the physical cues that it receives from its environment. Physical cues can include properties like the stiffness, or the microstructure of the substrate.
Dr. Watt’s lab has been investigating the effects of substrate topography and stiffness on cell differentiation when cells are cultured in a dish to determine what the so-called tipping point is for cell fate commitment. She discussed a technique that her lab has developed to isolate and study a single skin stem cell, where tiny adhesive islands are created on a gold-coated coverslip that can then be patterned with materials of different stiffness or shapes, allowing for extremely precise control of the cell microenvironment. By varying the pore size of the material that the cells were grown on, her team was able to determine that cells exert a mechanical force on the substrate and gauge the feedback they receive in order to make cell fate decisions, effectively converting the physical environmental signals into genome changes within the cell.
In addition to single cell adhesive islands, Dr. Watt has also developed what she called a human micro-epidermis “mini-tissue” of approximately 10 cells arranged in a doughnut-shaped ring of stem cells surrounding differentiated skin cells in the middle. These mini-tissues are placed on synthetic moulds that use polymers to pattern tiny three-dimensional hills and valleys. This configuration is used to mimic the topography, or shape, of the junction between the top layer of skin, the epidermis, and the deeper dermal layer that contains the stem cell population. By changing the shape of the peaks and troughs, her team can control where cells will differentiate or remain as stem cells, and they observed that cells on the peaks remained as stem cells while any cells in the troughs differentiated. This precise control over the topographical properties of their substrate allows them to study both what the tipping point for stem cell commitment is, and changes in stem cell behaviour due to aging or disease.
The second highlight was a talk given by Dr. Tommy Pashuck, a Research Assistant at Imperial College London. His work involves investigating the impact of substrate protein spacing on cell function and behaviour. In the body, cells need to be in contact with a substrate, be it other cells or the extracellular matrix (ECM) surrounding them. The ECM is highly heterogeneous in composition, depending on what tissue in the body you look at, but in general consists of a mix of different proteins, such as collagen, fibronectin and laminin, as well as sugars known as polysaccharides.
In order to interact with the surrounding environment, cells have a number of surface receptors, among them a class of proteins called integrins. How a cell will behave is greatly influenced by its ECM, and changes in the ECM are associated with an enormous range of diseases, from cardiovascular to inflammatory diseases of the kidney and liver. However, it is often difficult to recreate the complex arrangement of cells and ECM in order to study their interactions in the lab. Dr. Pashuck’s talk focused on the ECM protein fibronectin, and in particular two specific amino acid sequences that are found in fibronectin, which cell integrins bind to. The curious thing about these sequences is that they must be located approximately 3.5 nanometres (nm) apart on the fibronectin for functional cell integrin binding.
Dr. Pashuck showed that he could synthesize fibre networks made up of self-assembling protein sheets, which allow for the two key fibronectin sequences to be precisely placed one amino acid at a time at whatever location along the protein that is desired. He tested three locations for the sequences: 1) closer than 3.5 nm, 2) exactly 3.5 nm, and 3) farther than 3.5 nm, and observed that when cells were grown on the correctly spaced networks, their integrin expression was increased suggesting that the correct spacing was influencing cell behaviour. These fibre networks, because of their ability to be customized with any protein sequence, can be used to help answer the many questions still remaining about how cells interact with their environment.
Next up is part two of the WBC highlights, where I will cover some exciting cutting-edge research in cell delivery strategies!
Image: Viswanathan, P., M. Guvendiren, et al. (2016). “Mimicking the topography of the epidermal-dermal interface with elastomer substrates.” Integrative Biology 8(1): 21-29.
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