Unlike other potential targets of future stem cell approaches, there is already a current cell therapy for the treatment of type I diabetes. Indeed, islet transplantation has proven successful in inducing insulin independence for at least 1 year after the procedure. Progress in this discipline during the past 20 years has paved the way for stem cell-based therapies. Here we review the current state of the art of islet transplantation and examine the challenges that need to be addressed before a transition is made to stem cell-derived insulin-producing cells, with particular emphasis on the immunological aspects (rejection and autoimmunity) of type I diabetes.
Islet transplantation • Autoimmunity • Rejection • Nanoencapsulation • Diabetes
While the exploration of the mechanisms behind the development of the pancreas would have been fully warranted from a purely scientific point of view, it cannot be disputed that the prevalence of diabetes has very significantly stoked our progress in the field. Two more almost simultaneous circumstances have aligned to make pancreatic development one of the best studied examples of organogenesis: the advent of human embryonic stem cells and the development of protocols for the long-term survival and function of transplanted islets. Unlike many other conditions for which potential stem cell therapies have been conceived – but not put into practice yet – type I diabetes is arguably the perfect target of regenerative therapies: only one cell type needs to be replaced and there is an already existing cell therapy. The success of islet transplantation as a viable treatment of type I diabetes has led to the valid assumption that, if stem cells can be coaxed to produce insulin in a glucose-regulated manner, ensuing therapies are likely to work as well as native islets do. Such an approach would provide an immediate solution to the most pressing problem that stands in the way of the widespread implementation islet transplantation, namely the shortage of organs for islet processing and transplantation. Here we review the challenges and clinical perspectives of stem cell research in the context of the current status of islet transplantation.
Diabetes and Islet Transplantation
Type I diabetes is an autoimmune disorder whereby the immune system of the affected individual attacks and destroys the pancreatic beta cells that secrete insulin in response to elevated blood sugar levels. Because it is usually (but not always) diagnosed during childhood or early teenage years, it is also referred to as juvenile diabetes. Type II diabetes differs from it in that it does not usually start as an autoimmune response, but rather as a consequence of the inability of the cells of the body to respond adequately to otherwise normally synthesized and secreted insulin. In some cases, the beta cells will also produce less insulin than required to maintain glucose homeostasis. Type II diabetes tends to affect individuals at older ages, and it is commonly associated with obesity.
The only “conventional” treatment for type I diabetes is insulin administration. This is a life-saving procedure, but one that unfortunately fails to replicate the exquisite native regulation that islets exert over blood sugar levels. Years of exogenous insulin use cannot prevent the occurrence of complications that are generally based on a compromised integrity of the vasculature, including renal failure, amputations, and blindness.
Given the fact that only the islet can provide the glucose regulation required for long-term avoidance of complications, replacement beta cell therapies would be indicated not only for type I diabetes, but also for insulin-dependent type II diabetes and other conditions such as cystic fibrosis, hemochromatosis, liver cirrhosis, or iatrogenic diabetes after pancreatectomy. While whole pancreas transplantation is usually effective at reversing the symptoms of diabetes, it is rarely indicated as a treatment for the disease unless the patient is simultaneously receiving another organ (typically a kidney) or is already in an immunosuppressive regime. It is also considered major surgery and has a relatively high risk of complications. Islet transplantation, in contrast, is a much safer and easier procedure that offers the possibility of preconditioning the “organ” prior to transplantation. In short, this approach is based on the enzymatic digestion of a pancreas (from a deceased organ donor or from a living related one ) using a semiautomated method that makes use of mechanical agitation to separate the islets from the exocrine and ductal components of the pancreas .
A subsequent gradient centrifugation enriches for fractions with a high proportion of islets, which are subsequently cultured and infused through the portal vein of the patient using minimally invasive interventional radiology methods. The islets lodge in the vessels of the liver, where they get revascularized within 2–3 weeks.
In the case of allogenic islet transplantation (i.e., islets obtained from deceased donors), immunosuppression is necessary to prevent rejection. Before 2000, islet transplantation was successful only for a limited window of time, due to the deleterious effects of immunosuppressive steroids on islet cells. The development of a novel, glucocorticoid-free regime for islet transplantation enhanced very substantially the long-term viability and function of transplanted islets, with a great majority of patients reporting a significant improvement in their quality of life. Total insulin independence and full metabolic control is typically achieved after a critical mass of islets has been transplanted, which may require more than one donor.
Islet transplantation. Islets are isolated from a donor pancreas. Isolated preparations are typically cultured to allow islets to recover from the procedure, and then they are infused through the portal vein of recipients. This is an outpatient procedure, and requires the expertise of an interventional radiologist. Islets lodge in the microvasculature of the liver, and get revascularized within weeks
Tags: allogenic islet transplantation, Autoimmunity, cystic fibrosis, Diabetes, hemochromatosis, iatrogenic diabetes, immunological aspects, Islet transplantation, liver cirrhosis, Nanoencapsulation, Rejection, rejection and autoimmunity, stem cell-derived insulin-producing cells, treatment for type 1 diabetes