1. We developed a microfluidic platform to interrogate cell state. The platform consists of 16 channels, over each we have independent control. We optimised the cell encapsulation so that we have 3D control over the microenvironment for each cell inserted into the microfluidic device. We have now published this results, in Lab on a Chip (Mulas, Hodson, et al, Lab on a Chip, 2020).
2. One of the challenges we faced in our research so far was the unexpected problem of dealing with the immense amount of technical noise intrinsic to single cell RNA sequencing, which made our measurements of network entropy so far impossible. However, we have now developed models to account for the technical noise, and estimate uncertainty. These models are novel, and we believe they will be of great interest to the computational biology community. We are in the process of writing them up. Once we do, we will put it on a preprint server and begin the process of speaking to other experts in the field about how our new models can help others better understand the meaning of the data in this important and essential methodology.
3. In the course of our work developing the microfluidic platform to study stem cell fate transitions, we identified a signal that was essential for moving from one stem cell state to another. We performed a mechanistic study to determine exactly how that signal worked on the signalling pathways in stem cells to achieve this transition. This work is currently on a preprint server and under review at Review Commons (Mulas, et al, Biorxiv, 2023).
4.We developed a high-throughput cell stretcher, and were able to use it to show that embryonic stem (ES) cells are not responsive to mechanical cues, and only become so when they begin differentiating. We adapted the cell stretcher to perform calcium imaging and get a real-time readout of signalling as we apply active forces. This is now published in Open Biology (Verstreken, et al, Open Biology, 2019). We also adapted this tissue stretcher to collaborate with a group that used it to show that stretching oesophagus tissue leads to a change in stem cell activity during development (McGinn, et al, Nature Cell Biology, 2021).
5. We made significant progress on optimising and further developing the StemBond hydrogels. We used atomic force microscopy to disentangle stiffness from adhesion, and now understand how these hydrogels offer a significant improvement on previously published cell substrates. Specifically, we showed they are an improvement because the extracellular matrix binding on these gels is more stable than previous protocols, enabling far better and more stable engagement between cells and extracellular matrix (Labouesse, et al, Nature Communications, 2021). We also pushed it in a number of new directions. We published seminal work on the mechanisms of stem cell ageing using StemBond (Segel, et al, Nature, 2019). We are also making significant progress identifying the intracellular signalling pathways involved in cell fate transitions that are affected by mechanical signalling and how mechanics in turn affects cell fate choices in development and stem cells (de Belly, et al, Cell Stem Cell, 2021 and Yanagida, et al, Cell, 2022). We identified an important cross-talk between cell surface mechanics, which regulates signalling that instructs cell fate choice, and the mechanical environment. We have a European and American patent pending on StemBond, and once awarded are pushing it towards an international patent application. StemBond hydrogels have also formed the technology backbone of a new company called StemBond Therapeutics of which I am a cofounder, which is devoted to using mechanical control to better facilitate control of immune response in tissue.
