Stem cell-derived beta cells can now be grown in a dish, but they often die or fail to work properly after being transplanted into patients with type 1 diabetes. This project aims to keep those cells alive and functioning long enough to actually treat the disease. The problem is that lab-grown beta cells lack the supportive structure and chemical signals they would normally receive inside the pancreas. The researchers will use three strategies they have already tested on human islets: building miniature islets of controlled size and composition using microwell culture, pre-treating them with secretions from mesenchymal stromal cells, and coating the grafts with a nano-scale polymer layer that delivers anti-inflammatory drugs directly to the transplant site. If successful, this work could make stem cell transplants a reliable, long-term treatment for type 1 diabetes—freeing patients from constant blood sugar monitoring and insulin injections. The team has a clear route to the clinic through King’s College London’s existing human islet transplantation programme and an active MRC fellowship focused on translating fundamental beta cell biology into better patient outcomes.
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Differentiation protocols for generating β-like cells from stem cells (SC-β cells) are currently available and SC-β cells have now reached clinical trials. Our focus is further down the translational pathway to improve the function and survival of SC-β cells in the context of transplantation therapy using approaches that we have shown to be effective in primary human islets. We will first apply information from our spatial transcriptomic analysis of human fetal pancreas development to improve the generation of functional SC-β cells, and then apply our expertise in β cell/islet biology to ensure the optimal performance of SC-derived graft material. Primary β cells only perform appropriately within the islet environment so we will use microwell culture to generate SC-islets of defined size and cell composition, containing endogenous extracellular matrix generated by mesenchymal stromal cells (MSCs). We will assess improving the functional survival of SC-islets by pre-treatment with MSC secretory products. We will use conformal coating nanoencapsulation to deliver biotherapeutics with the SC-islet graft to improve SC-β cell function and to suppress localised inflammatory and thrombotic innate immune responses. Our experimental endpoints will include changes in SC-β cell gene/protein expression; functional parameters including insulin secretion and resistance to inflammatory insults; and the ability to maintain normoglycaemia in a mouse model of T1D. Together, these approaches will optimise the functional survival of SC-islet grafts. Our routes to clinical translation are clearly defined through the KCL Human Islet Transplantation programme and current MRC-CARP Fellowship funding to translate our basic science to improved clinical outcomes.
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