Improving islet engraftment by gene therapy

Abstract

Islet cell transplantation is currently the only feasible long-term treatment option for patients with type 1 diabetes. However, the majority of transplanted islets experience damage and apoptosis during the isolation process, a blood-mediated inflammatory microenvironment in the portal vein upon islet infusion, hypoxia induced by the low oxygenated milieu, and poor-revascularization-mediated lack of nutrients, and impaired hormone modulation in the local transplanted site. Strategies using genetic modification methods through overexpression or silencing of those proteins involved in promoting new formation of blood vessels or inhibition of apoptosis may overcome these hurdles and improve islet engraftment outcomes.

Figure 1

Structure of the pancreas. Pancreas tissue consists of both exocrine and endocrine glands. Islets of Langerhans mainly include α-, β-, and δ-cells. The islets are arranged in clusters associated with a dense network of capillaries. Most islet cells are directly in contact with blood vessels.

Figure 2

Factors controlling successful islet engraftment. The successful engraftment of transplanted islets is determined by both the ability to form new blood vessels and the capacity to limit apoptosis induced by both extrinsic (induced by extracellular inducers, such as inflammatory cytokines) and intrinsic (induced by intrinsic factors, such as hypoxia and nutrient deprivation) pathways. Proangiogenic factors such as VEGF, Ang-1, and ephrin promote angiogenesis. By contrast, antiangiogenic factors such as TSP-1 reduce this process.