Project ID CM-HD2023_20

ThemeCM-HD

Co Supervisor 1A Department of Diabetes, School of Cardiovascular and Metabolic Medicine & SciencesWebsite

Co Supervisor 1B Department of Diabetes, School of Cardiovascular and Metabolic Medicine & SciencesWebsite

Using mesenchymal stem cells to Improve 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, isolated islets are metabolically fragile and graft survival is compromised by the hypoxic, inflammatory host environment. 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, as suggested by the preliminary data shown in Figure 1. 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.

Objectives:
1. Year 1: Determine whether molecules secreted by human MSCs have beneficial effects on human islet/β-cell survival and function by measuring: insulin secretion; islet cell viability/apoptosis; mitochondrial function; gene expression.
2. Year 2: Assess human islet function in vivo in a novel mouse model of human islet transplantation, with subsequent analysis of graft morphology and function (see Fig.1). Comprehensive training in in vivo techniques will be provided.
3. 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.

One representative publication from each co-supervisor:

• Rackham CL, Hubber EL, Malik AN, Huang G-C, Choudhary P, King AFJ, Jones PM (2020) Optimising beta cell function through Mesenchymal Stromal Cell mediated mitochondria transfer.  Stem Cells 38(4): 574-584.  DOI: 10.1002/stem.3134 

• Austin A, Daniels Gatward L,  Cnop M,  Bowe J,  Sharp S,  Gentry C,  Andersson D, Bevan S,  Jones P,  King A. (2020) The KINGS mouse: a novel model of diabetes. Diabetes 69(12):2667-2677. doi: 10.2337/db20-0570.