Endothelial progenitor cell cotransplantation enhances islet engraftment by rapid revascularization.

Impaired revascularization of transplanted islets is a critical problem that leads to progressive islet loss. Since endothelial progenitor cells (EPCs) are known to aid neovascularization, we aimed to enhance islet engraftment by cotransplanting EPCs with islets. Porcine islets, with (islet-EPC group) or without (islet-only group) human cord blood-derived EPCs, were transplanted into diabetic nude mice. The islet-EPC group reached euglycemia by ∼11 days posttransplantation, whereas the islet-only group did not. Also, the islet-EPC group had a higher serum porcine insulin level than the islet-only group. Islets from the islet-EPC group were more rapidly revascularized at the early period of transplantation without increment of final capillary density at the fully revascularized graft. Enhanced revascularization rate in the islet-EPC group was mainly attributed to stimulating vascular endothelial growth factor-A production from the graft. The rapid revascularization by EPC cotransplantation led to better graft perfusion and recovery from hypoxia. EPC cotransplantation was also associated with greater ß-cell proliferation, probably by more basement membrane production and hepatocyte growth factor secretion. In conclusion, cotransplantation of EPCs and islets induces better islet engraftment by enhancing the rate of graft revascularization. These findings might provide a directly applicable tool to enhance the efficacy of islet transplantation in clinical practice.

Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress.

The exposure to acute or chronic endoplasmic reticulum (ER) stress has been known to induce dysfunction of islets, leading to apoptosis. The reduction of ER stress in islet isolation for transplantation is critical for islet protection. In this study, we investigated whether tauroursodeoxycholate (TUDCA) could inhibit ER stress induced by thapsigargin, and restore the decreased glucose stimulation index of islets. In pig islets, thapsigargin decreased the insulin secretion by high glucose stimulation in a time-dependent manner (1h, 1.35+/-0.16; 2h, 1.21+/-0.13; 4h, 1.17+/-0.16 vs. 0h, 1.81+/-0.15, n=4, p<0.05, respectively). However, the treatment of TUDCA restored the decreased insulin secretion index induced by thapsigargin (thapsigargin, 1.25+/-0.12 vs. thapsigargin+TUDCA, 2.13+/-0.19, n=5, p<0.05). Furthermore, the culture of isolated islets for 24h with TUDCA significantly reduced the rate of islet regression (37.4+/-5.8% vs. 14.5+/-6.4%, n=12, p<0.05). The treatment of TUDCA enhanced ATP contents in islets (27.2+/-3.2pmol/20IEQs vs. 21.7+/-2.8pmol/20IEQs, n=9, p<0.05). The insulin secretion index by high glucose stimulation is also increased by treatment of TUDCA (2.42+/-0.15 vs. 1.92+/-0.12, n=12, p<0.05). Taken together, we suggest that TUDCA could be a useful agent for islet protection in islet isolation for transplantation.

ATP measurement predicts porcine islet transplantation outcome in nude mice.

Current nude mice islet transplantation studies cannot be used prospectively. Therefore, to predict transplantation outcomes, reliable and rapid assays for islet quality assessment are warranted. This study evaluated the predictive power of the porcine islet ATP content on the outcomes of islet transplantation in nude mice. Here, we report that the ATP measurement using a small number of handpicked islets with a diameter of 100 to 150 mum is a good predictor of islet graft efficacy in nude mice. Using receiver-operator characteristic analysis, the area under the curve of the ATP content using a small number of handpicked islets was 0.867 (95% confidence interval 0.744-0.989, P<0.001). The sensitivity and the specificity measured were 83.3% and 73.3%, respectively. In conclusion, a simple and a rapid measurement of intraislet ATP content could be a promising substitute for current nude mice islet transplantation studies.