Outline of work
I am a currently Clinical Research Fellow in the second year of my PhD in cardiac regenerative medicine. My PhD is focused on understanding the mechanisms of arrhythmogenesis from stem cell therapy when pluripotent stem cell-derived cardiomyocytes are used to treat cardiac disease and whether the use of biomaterials can mitigate this. Biomaterials hold great promise for the cardiac regenerative medicine field by providing both a platform for both ex-vivo stem cell derived cardiomyocyte maturation and a protective environment for the cells during the immediate / early phase when they are integrating with the host. I am currently investigating how conductive polymers affect ex-vivo myocardial electrophysiology and performing in-vivo engineered heart tissue grafting experiments using a rabbit model of heart failure.
In the last few months I feel that I have been particularly fortunate to benefit from our BHF Regenerative network and our world class collaborators in Scotland and Germany. In the first year of my PhD, I underwent a period of training in complex surgical skills learning the rabbit model from Michael Dunne at Glasgow University in Professor Smith’s lab. I was then able to successfully implement the rabbit model at Imperial College with the help from our excellent CBS staff including Hannah Jones and Philip Rawson and both of our veterinary surgeons Lindsay Benson and Alisdair Gallie. Michael has been instrumental in the success of the model and visited Imperial for the first cases to ensure the implementation was a smooth as possible. We are in the process of developing the percutaneous myocardial infarction model and I look forward to working closely with the team in Glasgow in the future.
In December, I also visited Professor Eschenhagen’s lab in Hamburg, Germany and worked with Florian Weinberger. It was a very productive trip whereby we have now been able to upscale our engineered heart tissue at Imperial College to a size that is approaching the scale needed for the first-in-human studies. We have now begun our first rabbit grafting experiments at Imperial College. I will be analyzing the arrhythmic burden post grafting and performing ex-vivo optical mapping studies. We are also in the process of characterizing the larger engineered heart tissues. It is an exciting time to be working at the Imperial College BHF Regenerative Medicine Centre! A big thank you to our collaborators and to Thusharika Kodagoda in providing the cells to make the EHTs, and Tom Owen for your continuing help in assisting me with the first grafting experiments!
On collaborations with Cambridge, Glasgow and Hamburg
I have recently been working in collaboration with Amer Rana and his Ph.D student Baraa Kwielder in characterising the effects of different cell types in engineered heart tissues (EHTs). Amer and Baraa have perfected endothelial cell differentiation and have been able to make both coronary and endocardial cells. To characterise these cells I have been working in Sian Harding’s lab to test the effect of different endothelial cell subtypes on force production in EHTs.
EHTs were generated at Imperial with cells from Cambridge and non-invasive contractility measurements were made over time with technology from Thomas Eschenhagen’s lab in Hamburg. Therefore, in this project we have brought together expertise from three different labs, Amer Rana’s who is an expert in cell fate decisions specifically here dealing with endothelial cells, Thomas Eschenhagen who set up the EHT platform and characterises iPSCs, and Sian Harding’s group who produced the iPSC-CM and carried out the experiments. The EHT platform allowed us to automatically analyse in 3D force contractions in a semi-automated fashion with less chance for human error. The preliminary results of the first experiments were really encouraging with a significant increase in force seen in iPSC-CM EHTs co-cultured with endocardial cells but with no difference between iPSC-CM coronary endothelial cell EHTs and control.
This has important implications, one that supporting cell types can increase the force production of iPSC-CM, and two, that a difference can be found on force production when using endothelial cells with different phenotypes. We will be continuing this collaboration between the three labs, digging deeper to understand more about how different cell types contribute to hydrogel forces. This project has far-reaching aims, including to create a robust heart tissue construct in the lab: this will need collaboration from more labs in the centre to make a three-layered hydrogel. Lastly, because we are interested in regenerative medicine we aim to make hydrogels so that they can be transplanted into animals of heart failure. The cell therapy project is being carried out currently with much larger hydrogels, and we hope now to improve these too based on the results of adding in endothelial cells.
I am also working in collaboration with Godfrey Smith’s lab in Glasgow and Thomas Eschenhagen’s lab in Hamburg to work on a larger animal model of myocardial infarction as a test bed for EHTs. The project lead for this is Richard Jabbour who has brought the rabbit model from Glasgow and large EHT technology from Hamburg so that in Sian Harding’s lab in London we can start to test if hydrogels can help ameliorate the signs of heart failure. This PhD project is in its 2nd year and the model has been set up at Imperial and large EHTs are being produced so that the first few hydrogels are just being tested for iPSC-CM retention. Firstly, we are testing whether large EHTs can be retained at early time points and are setting up optical mapping so that grafted hearts can be analysed on a whole heart Langendorff system. After the initial optimisation phase of cell retention, we will put iPSC-CM large EHTs on rabbits with myocardial infarcts to test whether hydrogels can be used to repair damage in a large animal model.
The work written about here could not have been possible without the excellent communication between the labs and the trips made around the country and to Germany to share key knowledge and expertise. Special mention also has to go to Thusharika Kodagoda and the stem cell team at Imperial, because stem cells are like babies and need loving every day.