Dynamic surfaces to mimic mesenchymal stem cell niche functions

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The stem cell niche acts to control stem cell growth (control self-renewal) and differentiation in a dynamic manner. Current developments in materials science, focused on a key regenerative stem cell type, the mesenchymal stem cell, have allowed us to regulate both self-renewal (to allow us to grow multipotent populations by preventing phenotypical drift to e.g. fibroblasts) and to target differentiation to desired functional cell types. The materials do this by controlling cell adhesion and intracellular tension important for regulation of biochemistry and transcription. However, the materials are designed either for growth or for differentiation and lack the flexibility to support both stem cell functions.
We have developed enzyme switchable surfaces that can be used to control cell adhesion in an on-demand manner and will exploit this technology to develop dynamic materials for stem cell culture. In the proposal, we will create an initial surface that control adhesion to promote self-renewal and hence growth as multipotent stem cells allowing us to achieve large numbers of true stem cells. This will be achieved by controlling the length of polyethyleneglycol (PEG) chains that block cells from adhering to the underlying differentiation surface (e.g. RGD, t-butyl, single peptides). Enzymatic cleavage of the PEG chains will then expose the differentiation surface to the mesenchymal stem cells on demand. Hence we will have fabricated surfaces that allow the cells to grow to large numbers and then change to functional cells in a controllable manner mimicking niche dynamics.
Finally, we will explore the possibility of using secreated enzymes (e.g. matrix metalloproteases) which have changes expression profiles in dense cultures to switch the surfaces as the cells grow more confluent (i.e. the enzymatic switch would automatically happen when enough stem cells were present).

Initially impact will be academic as this is a very new concept. However, it is recognized that a step change is required to facilitate therapeutic use of stem cells as traditional cell culture plastics are not suitable and soluble factor chemistry is proving complex and can add artefact and so this research is vital. The use of niche biomimicry (stem cells responding on demand) will capture the imagination of science in general and we will target high-impact journals to ensure maximum dissemination to the community.

It is noteworthy that the applicants have strong track record in taking fundamental research observations towards commercialisation through spin-out and licensing. We will, again, look to protect IP and then exploit this towards next generation stem cell culture products. Such products will impact on cell culture industry as new products for stem cell growth are made, biotechnology industry will benefit as capacity for stem cell growth increases and autologous stem cell therapies become available. Tissue engineering will benefit as lots of high-quality cells from small isolations can be achieved and incorporated in their scaffold materials. Finally, clinicians and the public will benefit from therapies enabled by our platform technologies. This exploitation will be ongoing through the grant.

Thus, non-academic beneficiaries will include:
1) Industry - the development of new materials will fuel stem cell research. Stem cells themselves can now be purchased from catalogues and we will provide new consumables for purchase alongside the cells to aid research.
2) Clinic - most clinicians now accept that new biomaterials coupled to stem cells and nanotechnology will be important in the medium-term future. We believe it is pivotal for clinicians to engage with early-stage research to inform a realistic compromise between material function and clinical application.
3) Patients - the public are interested in (and actually expect) the delivery of stem cell therapies and our surfaces hold the potential to help deliver these therapies.
4) Public - through our public outreach in schools (Dalby has close ties with Lenzie Academy). We will inspire students to consider a career in research and academia. There is a poor understanding amongst school children taking career decision about what academics do beyond teaching and the best students choose medicine as a default career. However, basic science can be just as rewarding, if not more so, and school leavers should be aware of the possibility to help change medicine through academic research. It is, we believe, encumbent on us to stimulate, inform and inspire the next generation as an informed public base will lead to an informed science culture. Dalby had participated in stem cell debates with the public (for BBSRC, EPSRC and Royal Society of Edinburgh) and will continue this work.

To support this impact we will use our surgical links with Mr Meek through the Glasgow Orthopaedic Research Initiative and also with Prof Hart for plastic and reconstructive surgical links. They are both keen to engage with fundamental science to help facilitate translation.