Omentum Is Better Site Than Kidney Capsule for Growth, Differentiation, and Vascularization of Immature Porcine β-Cell Implants in Immunodeficient Rats

Islet intraportal transplantation is since long considered as therapy for type 1 diabetes (1). Clinical proof-of-concept has been provided since the early 1980s and initiated clinical trials worldwide (2–4). In most trials with human donor islets, the liver is still used as implant site, although there is growing awareness that this site is not optimal (5). It has been shown that several of its immunologic, anatomic, and physiologic features contribute to a significant early graft loss and β-cell dysfunction. Moreover, because this implant site is inaccessible, it can also not be considered when it comes to the use of alternative β-cell sources, such as stem cell–derived β cells or the use of xenografts (6–8). Several alternative sites have been tested in animal models to improve engraftment and long-term survival and to minimize surgical complications (6, 8). Few of these alternative sites hold the potential to be translated into clinical trials, and in general, evidence of posttransplantation functions better than those reached after intraportal infusion are lacking. The present study further assesses the omentum as implant site. This site was previously shown successful for rat islet isografts, which is in itself not particular because these preparations have functioned well in many sites (9, 10). When testing human islet cell grafts in diabetic immunodeficient rats, we found a better survival in the omentum than in the liver: omental implants exhibited little infiltration and were capable to correct hyperglycemia, whereas intraportal implants lost function after a heavy inflammatory infiltration (11). We now assess whether the omental site would also provide an adequate environment for growth of the β-cell mass as is known to occur in implants of immature pancreatic cell preparations (12–14). In a previous study, we have shown the growth potential of perinatal porcine β-cell grafts implanted under the kidney capsule of nude mice (15). The implants became structurally organized as homogenous endocrine clusters with predominantly insulin-positive cells and few other endocrine cells in the periphery; the increase in β-cell mass generated the potency to normalize diabetes (15, 16). Efficient revascularization is considered to be a prerequisite for this process (17). Within 2 days after implantation, we recognized the first endothelial cells and small blood vessels in the proximity of the implants; the revascularization process, however, proceeded beyond the 20-week study period (15, 18). It is conceivable that the rapidity and extent of this process determines initial engraftment as well as subsequent adaptive growth. Because the omentum is well vascularized and has been described as a rich source of angiogenic and neurogenic factors (19–21), we wanted to compare the growth of immature porcine β-cell grafts in omentum and kidney and relate it to the vessel density that has developed in both implants. Implants in the omentum reached vessel densities comparable with those in endogenous adult porcine islets within 10 weeks after implantation, which was not the case in the kidney subcapsular space. In parallel, implant volumes were increased reflecting a beneficial effect on β-cell proliferation and numbers as well as on cellular insulin content. Our data elaborate our prior findings with human islets implants and add further support on the potential use of the omentum as an alternative site for islet transplantation. Whether the omentum could offer an alternative to intraportal transplantation in humans remains to be evaluated.