Co-Transplanting Mesenchymal Stem Cells With Islets
Dr. Greg Korbutt
Recent long-term metabolic follow-up of human islet transplant recipients indicates marked reduction in human islet graft function with only 10% of the recipients maintaining insulin independence at 5 years post-transplant. The decline in insulin independence rates seen in clinical islet transplantation is currently not fully understood, but is likely complex. Detrimental factors include recurrent β-cell autoimmunity, allograft rejection, metabolic exhaustion, chronic islet toxicity of immunosuppressive drugs, limitations of the intra-portal site, and possibly low numbers of intra-graft potential β-cell precursors to provide a source of new insulin-producing cells. Strategies designed to maximize islet survival, minimize inflammation of the initial islet mass and to allow transplantation into more suitable sites are likely to have a major impact in enhancing long-term clinical outcomes. Multipotent mesenchymal stromal cells (MSCs) have immunoregulatory as well as regenerative properties and are found in bone marrow and connective tissue. MSCs have been documented to decrease inflammation, promote tissue regeneration and blood vessel growth as well as modulate the in vivo immune response.
Since both human islets and MSCs are currently being used separately for treating Type 1 diabetes, it is a logical clinical translational strategy to combine them to improve islet graft survival. A project is currently underway in my lab to determine if co-transplantation of MSCs with human islets will prolong islet graft survival and improve islet engraftment by locally secreting protective factors that promote vascularization, cell survival and regeneration, as well as reduce immune reactivity to the islets. Results from our in vitro co-cultures of MSCs and islets have recently shown that MSCs protect human islets from exposure to pro-inflammatory cytokines and help islets retain their insulin-secreting function by reducing inflammation. The next phase of the project is to determine whether MSCs will show the same protective effects on human islets when transplanted in vivo. To test this, a study is underway where MSCs are co-transplanted with human islets in a diabetic mouse model with a humanized immune system, which mimics human islet transplant.