Research Projects

Diabetes affects more than ~537 million people, including ~77 million Indians, costing trillions of US dollars to the world economy 3. However, despite technological advancements, maintaining normal glucose homeostasis is very challenging and results in debilitating secondary complications such as organ failure and death by coma 4,5. Islet transplantation is an effective method of diabetes cure 6. It proves that the endogenous production of insulin and glucagon provides an effective and safe method for treatment. Nonetheless, an imbalance in availability versus demand deprives millions of patients of a better quality of life. Recent advances in stem cells with methods generating insulin-producing beta-cells 7-11, provide a tangible alternative for cell replacement therapies and diabetes cure. Insulin-producing cells being tested in clinical trials are showing promising results 2,12, however, they are faced with critical challenges (Problem statement) including a) the requirement of high dose of cells due to poor differentiation efficiency, b) compromised glucose-stimulated insulin secretion due to incomplete maturation, and c) poor graft survival due to delayed vascularisation. Despite remarkable progress, the formation of a full complement replicating all aspects of native Islet function has remained elusive. Development of the pancreas is guided by core transcriptional machinery and factors including Isl1, Nkx6.1, Ngn3, Pdx1, Hedgehog, FGF, TGF-β, BMP, Wnt, Notch, Retinoic Acid 13-15 and several other lesser-known molecular cues. Moreover, crosstalk from adjacent tissues such as cardiac mesoderm and vascular components provide molecular cues for differentiation and function 16,17. We hypothesise that endogenous niche with homo- and hetero-typic interactions between endocrine and vascular cells have a profound effect on stem cell-derived beta-cell function. The vision of this program is to develop novel approaches for engineering human pluripotent stem cells (hPSCs)-derived Islet organoids and validate its function in the humanized NXG-HIS mouse model of diabetes using our knowledge from Developmental Biology and stem cells. We have demonstrated an ameliorating effect of beta-cell niche on its function in dish 11 and have identified critical signalling cues using single-cell transcriptional profiling. Under this program, we will refine our model to recapitulate endogenous cellular interactions, which we propose will enhance post-implantation integration, survival and function. Further, considering the epigenetic variability and its effect on precision medicine, we aim to test our model on indigenously developed stem cells. Significance – Under this program, we validate the safety and efficacy of stem cell medicine for diabetes in animal models. The outcomes will help in establishing clinical collaborations and transition to the clinics, thereby providing hope for a better quality of life for patients living with diabetes.