Prof. Henrik Semb (ITS, HMGU) in collaboration with Dr. Greg Korbutt and Dr. Andrew Pepper (University of Alberta)
Assessing safety and efficacy of vascularised human stem-cell derived beta cells in vivo
Research interest and project description:
Advances in islet transplantation have established the proof-of-concept for this therapy to emerge as a viable option to treat patients with type 1 diabetes (T1D). However, donor scarcity and poor islet survival restrict this therapeutic modality to fewer patients. hESC-derived beta cells can replace human islets for transplantation to diabetic patients due to their capacity to secrete insulin in a glucose-regulated manner and expand limitlessly. The transplant site of hESC-derived beta cell therapies can pose challenges, as it should be accessible to retrieving grafts, in case of neoplastic formation (safety), and in parallel to generate a vascularised microenvironment ensuring long-term engraftment and subsequent reversal of diabetes (efficacy).
The PhD project will address the challenges to develop a safe and effective cell-based product for T1D patients. Specifically, the project will focus on transplanting hESC-derived beta cells in a subcutaneous pre-vascularised matrix thus improving long-term beta cell survival, engraftment and function with the ultimate goal of correcting diabetes 1,2,3,4.,5 Furthermore, pre-and post-transplant grafts will be fully assessed for the presence of any neoplastic formation and any changes in their phenotypic and maturation status.
This study represents an innovative approach to generate a vascularised beta- cell modality to establish long-term normoglycemia for T1D patients.
- Pepper AR, Gala-Lopez B, Pawlick R et al. A prevascularised subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol. 2015; 33 (5): 518-523
- Pepper AR, Pawlick R, Bruni A et al., Transplantation of human pancreatic endoderm cells reverses diabetes post transplantation in a prevascularised subcutaneous site. Stem Cell Reports. 2017; 8(6): 1689-1700
- Pepper AR, Bruni A, et al. Posttransplant characterization of long-term functional hESC-derived pancreatic endoderm grafts. Diabetes. 2019; 68: 953-962
- Ameri J, Borup R, et al. Efficient generation of glucose-responsive beta cells form isolated GP2+ human pancreatic progenitors. Cell Reports. 2017; 19(1): 36-49
- Mamidi A, Prawiro C, et al. Mechanosignalling via integrins directs fate decisions of pancreatic progenitors. Nature. 2018; 564(7734):114-118