Generation and characterization of pseudo-islets for beta-cell replacement
PhD Student: Hany AbdelGawad AbdelSalam Abdel-Gawad
Supervisor at TUD: Barbara Ludwig
Supervisor at KCL: Peter Jones
Start Date: 24.07.2020
Islet transplantation in patients with insulin-deficient diabetes mellitus enables restoration of glucose-regulated endogenous insulin secretion, improves quality of life, and reduces secondary complications. However, current clinically available strategies are limited by donor organ scarcity, immunogenicity, and dissatisfying long-term function. To overcome these obstacles, we are actively developing strategies for islet macroencapsulation that provide sufficient immune-isolation while maintaining islet graft function. A close collaboration with the Leibniz-Institute for Polymer Research Dresden, offers us the means to explore the safe utilization of alternative islet sources such as xenogeneic islets. Essential parameters for successful islet microencapsulation are islet purity, size distribution, density and diffusion properties within the device.
We hypothesize that size-optimized islet clusters from different species are superior to native islets with regard to functional potency and suitability for encapsulation purposes. Therefore, this project will focus primarily on the optimization of the size distribution because of its impact on oxygen demands. There are multiple indications suggesting that smaller pancreatic islets, independently of the species, survive longer and have improved insulin secretion due to reduced susceptibility ischemia. Theoretical models based on oxygen consumption rate and nutrient diffusion throughout the islets predict that islet function is optimal with a diameter of 100 µm. Since oxygen consumption rates and diffusion characteristics are essential to maximize cell density and function within the encapsulation device, the generation of islets with optimal dimensions may have significant beneficial effects on islet survival after transplantation and could help to overcome nutrient diffusion limitations. The control of islet sizes is easily achieved as it relies on the self-assembly capacity of its endocrine cells. Essentially, isolated islets are dissociated into single cells and subsequently reaggregated into three-dimensional, homogenous, size-defined aggregates/ islet-like clusters, so called Pseudo-Islets. In addition to improved function, these pseudo-islets also seem to have attenuated immunogenicity following transplantation.
In conclusion, the use of xenogeneic pseudo-islets shows an exciting promise to positively impact the therapeutic options of Type 1 Diabetic patients.
Publication:
Protection from doxorubicin-induced nephrotoxicity by clindamycin: novel antioxidant, anti-inflammatory and anti-apoptotic roles. K.M. Ibrahim, E.M. Mantawy, M.M. Elanany, H.S. Abdelgawad, N.M. Khalifa, R.H. Hussien, N.N. El-Agroudy, E. El-Demerdash. Naunyn Schmiedebergs Arch Pharmacol. 2020;393:739-748.