The pancreas niche: defining the in situ identity and therapeutic potential of pancreatic stromal cells in diabetes

Context Our bodies have remarkable defence mechanisms to protect our tissues from immune attack. Every tissue and organ harbours unique and specialised stem/stromal cells to help keep our vital organs functioning. These naturally reparative stromal cells sense “danger signals” within their native environment and respond by producing anti-inflammatory and immunomodulatory therapeutics. Clinically, stromal cells (termed Mesenchymal Stromal Cells (MSCs)) are isolated from tissues such as bone marrow and fat so that they can be used to treat a wide range of inflammatory and autoimmune conditions including type 1 diabetes (T1D). MSCs preserve the function of insulin producing islet beta-cells in the pancreas of individuals with recently diagnosed T1D following their infusion into the blood stream. Emerging reports have also begun to establish the therapeutic potential of distinct pancreatic stromal cell populations including Pancreatic-MSCs and Pancreatic Stellate Cells (PSCs), to act as “islet helper cells”, similar to the more established functions of MSCs derived from extra-pancreatic tissues (including bone marrow and fat). Challenge the project addresses We know little about the role of endogenous/native PSCs in maintaining pancreatic islet survival in response to immune attack during T1D development. Understanding whether pancreatic stromal cells can survive during T1D progression is important because it will help us to understand the pancreatic stromal cell related changes that we can target therapeutically to help delay or prevent the development of T1D. Our project will further inform how distinct pancreatic stromal cell populations (PSCs and pancreatic-MSCs) may be used to support the long-term survival of transplanted islets/stem cell-derived islets (SC-islets) to treat individuals with already established T1D. Aims and objectives By virtue of our access to rare T1D and control donor pancreas tissue, we will investigate pancreatic stromal cell populations in samples from individuals with recent-onset T1D where islet immune attack is still ongoing. We will use advanced imaging studies to determine T1D-related alterations in PSC number, location and islet-protective characteristics. We will investigate whether PSCs produce therapeutic factors that help to prevent harmful immune cell infiltration and destruction of insulin producing islet beta-cells during T1D development. In parallel, we will use “ex vivo” (outside of the body) experiments that model/mimic T1D pathogenesis/development and islet transplantation using defined pro-inflammatory stressors (cytokines). We aim to determine how pancreatic stromal cells (that have been isolated from the pancreas and grown in the laboratory) support the survival of isolated islets. We will establish how pancreatic stromal cells alter their DNA/gene expression to define the therapeutic factors through which PSCs/pancreatic-MSCs help in T1D. Potential applications and benefits Pancreatic stromal cells are a by-product of the clinical islet isolation/transplantation procedure. They represent a feasible source of “islet helper cells” with real potential to prevent the unwanted loss of islets/SC-islets after transplantation. For individuals with established T1D, islet or SC-islet transplantation offers the perfect treatment for continuous, real-time, insulin delivery avoiding short-term risks of low blood glucose and longer-term risks of high blood glucose. Using pancreatic stromal cells in transplantation may benefit individual islet graft recipients and allow the treatment of many more people with T1D. Reducing inflammation and preventing the loss of beta-cells with pancreatic “islet-helper cells” also has potential to improve quality of life for many people who would otherwise develop T1D.