Extracellular Vesicles and Islet Transplantation Strategies
By: Zach Jones
What is Islet Transplantation?
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing beta cells in the islet of Langerhaans. One potential therapy for the disease is implanting new beta cells in T1D patients, an experimental procedure which has produced some success. Currently the risks of the implantation – mainly procedure-related injuries and consequences of the necessary inductive immunosuppressants – outweigh the benefits, and the therapy would only be considered for a select number of patients in clinical trials or those with an impaired awareness of hypoglycemia.
But other implant procedures like kidney transplants are completed relatively frequently and with much success. Moreover, during pregnancy, the body naturally creates a placenta (in other words it implants a placenta) in the upper uterus, which provides nutrients to the baby. Looking at the success of other implantation procedures including the naturally occuring placenta implantation might shed light on how to make islet transplantation more favorable. The answer might come from, in part, small lipid-bilayer particles called extracellular vesicles (EVs).
Current islet implantation techniques are risky or fail for a number of reasons. Implants typically provoke inflammatory responses from patients’ immune systems, requiring that immunosuppressive drugs be taken for life. Otherwise, the immune system would quickly destroy the implanted cells. Furthermore, a lifetime course of immunosuppressant drugs decreases the immune system’s ability to fight off pathogens like the seasonal flu and increases the risk of developing cancer.
Extracellular Vesicles to the Rescue! The Promise of EVs for Islet Implantation
EVs, typically used by cells for intercellular signaling and cargo transport, show promise in modulating the immune response after implantation. The vesicles transmit “messages” to cells by transporting RNA and DNA between cells or activating ligands with proteins on the outside of the lipid bilayer. The EVs from immune cells naturally regulate immune responses via these signaling pathways.
Researchers might take advantage of this by isolating EVs from mesenchymal stem cells (MSCs) that signal for anti-inflammatory processes. In fact, EVs already show promise in rat models. For example, Gregorini et al found that the perfusion of isolated kidneys with MSC EVs prevented ischaemic injury.
But protection from the immune system isn’t the only requirement for an islet implantation — the implant also needs enough oxygen and nutrients. In the body, the vasculature provides oxygen and nutrients to cells, but because implants aren’t connected to these blood vessels, they can wither away from hypoxia or starvation. During placental development, EVs are naturally released to facilitate communication between different cell types, in part to supply the baby with nutrients. In a review article, Kholia et al noted that EVs can promote angiogenesis by secreting various interleukins and growth factors. If that’s the case, then EVs might be used during islet transplants to promote survival, growth and insulin production.
Bioengineering of EVs with specific targets and cargo is already possible, as Martin Fussenger at ETH Zurich wrote in a review article. A better understanding of placental development is warranted to find applications of EVs during transplantation. One group of researchers at Stanford in the obstetrics and gynecology department are up to the task and have begun the 3D modelling of human placental development. If successful, the group could pave the way for using placental development mechanisms for other types of translations, including islets.