Human blood outgrowth endothelial cells improve islet survival and function when co-transplanted in a mouse model of diabetes

Abstract

Aims/hypothesis As current islet-transplantation protocols suffer from significant graft loss and dysfunction, strategies to sustain the long-term benefits of this therapy are required. Rapid and adequate oxygen and nutrient delivery by blood vessels improves islet engraftment and function. The present report evaluated a potentially beneficial effect of adult human blood outgrowth endothelial cells (BOEC) on islet graft vascularisation and function. Methods Human BOEC, 5×10 5 , were co-transplanted with a rat marginal-islet graft under the kidney capsule of hyperglycaemic NOD severe combined immunodeficiency (SCID) mice, and the effect on metabolic outcome was evaluated. Results Although vessel density remained unaffected, cotransplantation of islets with BOEC resulted in a significant and specific improvement of glycaemia and increased plasma C-peptide. Moreover, in contrast to control mice, BOEC recipients displayed reduced beta cell death and increases in body weight, beta cell proliferation and graft-vessel and beta cell volume. In vivo cell tracing demonstrated that BOEC remain at the site of transplantation and do not expand. The potential clinical applicability was underscored by the observed metabolic benefit of co-transplanting islets with BOEC derived from a type 1 diabetes patient. Conclusions/interpretation The present data support the use of autologous BOEC in translational studies that aim to improve current islet-transplantation protocols for the treatment of brittle type 1 diabetes.

Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

“…In addition, the frequent changes in blood glucose levels and high glucose concentrations are known to be deleterious to the islets. Therefore, many studies have pursued alternative sites with a more adequate microenvironment for pancreatic islet transplantation, such as organs (renal subcapsule, omentum, peritoneum, subcutaneous site, muscle) (14-16), various vascular sites (celiac artery, vein, spleen, lung) (17,18), immunoprivileged sites (testis, thymus) (19,20), or devices and capsules (21)(22)(23)(24)(25). These may optimize engraftment, survival, and function as well as decrease immunogenicity and promote proliferation and regeneration.…”

Reversal of hyperglycemia in diabetic mice by a marginal islet mass together with human blood outgrowth endothelial cells is independent of the delivery technique and blood clot-induced processes

“…4 To evaluate whether BOEC also exert a beneficial effect on marginal islet transplantation without prior entrapment of the graft in a blood clot, the experimental setup of marginal islet mass transplantation was applied to transplantation via a tubing technique. Sixty, 75, or 150 islets were transplanted by inserting a polyethylene tubing with 0.58mm inner diameter (PE-50) underneath the kidney capsule of immune deficient mice with alloxan-induced diabetes.…”

“…2,3 In a search to improve currently available islet transplantation protocols, we recently reported that human blood outgrowth endothelial cells (BOEC) promote β-cell survival, proliferation, and glycometabolic control when co-engrafted with a marginal islet graft in the renal subcapsular space. 4 As the islet-cell mixture was entrapped in a blood clot prior to engraftment, thereby initiating IBMIR-like processes and since endothelial and endothelial colony forming cells have been demonstrated to Keywords: diabetes, mouse, islets, transplantation, tubing, blood clot, endothelial cells Abbreviations: BOEC, human blood outgrowth endothelial cells; IBMIR, instant blood-mediated inflammatory response; NOD SCID, non-obese diabetic severe combined immunodeficient; iv, intravenous; ALX, alloxan monohydrate; BW, bodyweight; FCS, fetal calf serum; BSA, bovine serum albumin; PBS, phosphate-buffered saline; NaCl, sodium chloride; PE-50, polyethylene tubing; Na-EDTA, sodium-ethylenediaminetetraacetic acid; RIA, radio-immuno assay; PTx, days after transplantation; islet x , graft consisting of X islets; mmol/L, millimolar per liter; islet X+BOEC , graft consisting of X islets supplemented with 5x10 5 BOEC…”

“…As we previously reported a beneficial effect of BOEC on islet engraftment using the blood clot technique, 4 we aimed to evaluate whether BOEC also favor the glycometabolic outcome of islet transplantation when co-engrafted via a tubing system. Demonstrating a positive effect of BOEC in the latter experimental condition further supports BOEC as valuable graft supporting cells for islet transplantation.…”

Beating diabetes: strategies to improve pancreatic islet transplantation

“…A recent study showed that infusion of sertoli cells followed by transplantation of islets that were coated with endothelial cells resulted in enhanced islet graft survival and function in an in vivo rat model, compared to untreated islets [67]. In addition, co-transplantation of rat islets with human blood outgrowth endothelial cells in a mouse model improved glycemic levels, increased plasma c-peptide and reduced beta-cell death, compared transplantation of islets alone [68]. These studies suggest that adding exogenous endothelial cells may facilitate survival and function of islets and tissue engineered islet-like clusters.…”