Project ID CM-HD2024_04


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Diabetes & Obesity themeWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Diabetes & Obesity themeWebsite

Additional Supervisor Dr Simon Pitchford

Improving human islet transplantation as a cure for Type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disorder in which the destruction of insulin-secreting β-cells leads to an inability to regulate blood glucose appropriately, leading to a range of pathological consequences. We currently treat the symptoms of T1D with daily administration of exogenous insulin, but recent advances in human islet transplantation protocols offer the potential of a permanent cure for T1D. However, islet grafts are metabolically fragile and graft survival is compromised by the hypoxic, inflammatory host environment, such that up to 70% of graft function is lost in the immediate post-transplantation period. We have shown that mesenchymal stromal cells (MSCs) have beneficial effects on islet graft functional survival in animal models of diabetes, and we have identified a cocktail of MSC-derived molecules that contribute to this. This project will determine whether these beneficial effects translate to clinically relevant human islets and thus have the potential to improve the outcomes of human islet transplantation as a treatment for T1D. This is a translational project in which data generated from experimental studies will be used to improve human islet transplantation as a therapy for type 1 diabetes.

Experimental objectives:
Year 1: Determine whether molecules secreted by human MSCs have beneficial effects on human islet/β-cell survival and function using a range of in vitro functional. We will assess changes in human beta cell gene expression using scRNAseq and bioinformatic analysis. Training will be provided by the supervisors and the School.
Year 2: Assess human islet function in vivo in a novel mouse model of human islet transplantation. Comprehensive training in in vivo techniques will be provided.
Year 3: A route to translation: the student will work with co-supervisor Dr Sufyan Hussain to determine how best to move to work to a clinical setting, offering experience into how the translation process works in the real world.

Representative Publications

The KINGS mouse: a novel model of diabetes. Austin A, Daniels Gatward L, Cnop M, Bowe J, Sharp S, Gentry C, Andersson D, Bevan S, Jones P, King A. Diabetes 69(12):2667-2677, 2020. doi: 10.2337/db20-0570. The glucose tolerance test in mice: sex, drugs and protocol. Kennard MR, Nandi M, Chapple S, King AJF. Diabetes Obes Metab, 24:2241-2252, 2021. DOI: 10.1111/dom.14811, 2022 Composite Mesenchymal Stromal Cell Islets: Implications for Transplantation via the Clinically Preferred Intraportal Route. Rackham CL, Dhadda PK, Simpson SJS, Godazgar M, King AJF, Jones PM. Transplant Direct. 19;4(4):e354. doi: 10.1097/TXD.0000000000000778
Protecting islet functional viability using mesenchymal stromal cells. Hubber EL, Rackham CL, Jones PM Stem Cells Translational Medicine 10:674-680, 2021 DOI: 10.1002/sctm.20-0466. Annexin A1 is a key modulator of MSC-mediated improvements in islet function. Rackham CL, Vargas A, Hawkes RG, Amisten S, Persaud SJ, Austin AL, King AJF, Jones PM. Diabetes 65, 129-139, 2016. doi: 10.2337/db15-0990. Characterisation of the effects of mesenchymal stromal cells on mouse and human islet function. Arzouni AA, Vargas-Seymour A, Dhadda P, Huang G-C, Choudhary P, King AJF and Jones PM. Journal of Stem cells Translational Medicine, 8: 935-944, 2019. doi: 10.1002/sctm.19-0023