(73c) Cell and Tissue-Based Therapies for Insulin-Dependent Diabetes

A living biological substitute for treatment of insulin-dependent diabetes has significant potential in providing a less invasive, more physiologic regulation of blood glucose levels than insulin injections.  The critical technologies needed for such a substitute depend strongly on the type of cells used.  With cells from another individual (allogeneic) or another species (xenogeneic), encapsulation in semipermeable barriers improves immune acceptance, as it inhibits passage of antibodies and excludes cytotoxic cells of the host.  However, immune protection is not complete, and immune suppression may still be needed to prolong survival of the graft.  Non-pancreatic cells from the same patient (autologous), targeted by gene transfer vectors or retrieved surgically and genetically engineered ex vivobefore being returned to the patient, may relax the immune acceptance problems but pose challenges regarding the amount and kinetics of insulin secretion in response to physiologic stimuli.  Stem and progenitor cells constitute another promising cell source, however, their reproducible differentiation into pancreatic cells presents significant challenges.

In our laboratory, we focus on encapsulated allo- and xenogeneic pancreatic cells and on non-pancreatic cells genetically engineered to secrete insulin in response to physiologic stimuli.  With encapsulated cells, we are developing methods to improve immunoprotection by combining the semipermeable barrier with the local presentation and delivery of pro-survival and insulinotropic factors.  Furthermore, we develop technologies for cryopreservation of encapsulated cells and for monitoring grafts in minimally invasive or non-invasive ways.  Of particular importance is the use of 19F nuclear magnetic resonance spectroscopy to measure dissolved oxygen levels in vivo.  One of our major findings is that the murine peritoneal environment, where encapsulated cells are commonly transplanted, is hypoxic and it becomes more hypoxic upon transplantation of islets or other insulin-secreting cells.  With non-pancreatic cells, we genetically engineer hepatic and intestinal endocrine L cells for insulin secretion.  These cells are potentially autologous, however, they pose challenges regarding the amount and kinetics of secreted insulin.  Results from experiments involving transplantation of murine, insulin-secreting L cells in diabetic mice demonstrated that the graft had a significant positive effect on the glycemic regulation of the animals, however, it did not cure diabetes.   The potential and challenges for developing clinical therapies based on these approaches will be discussed.