Pancreatic Islet Transplantation Using Vascularised Chambers Containing Nerve Growth Factor Ameliorates Hyperglycaemia in Diabetic Mice

Abstract

Intraportal islet transplantation has shown initial promise for the treatment of type 1 diabetes. However, the portal vein site is associated with complications such as thrombosis and hepatic steatosis, leading to transplant failure. The aims of this study were to (1) test the feasibility of an alternative islet transplantation method that utilises a FDA-approved gelatin sponge as a novel islet carrier and (2) assess if exogenous addition of nerve growth factor (NGF) has any additional beneficial effects on graft performance in diabetic mice. Mice were rendered diabetic by a single intraperitoneal injection of streptozotocin. Five hundred syngeneic islets were seeded onto a Gelitaspon® disc in the presence or absence of NGF, and placed into a silicone chamber surrounding the femoral neurovascular pedicle. Islet function was assessed by weekly monitoring of blood glucose levels and an intraperitoneal glucose tolerance test performed at the end of the study. Chambers were harvested for further histological analysis. Four of five mice transplanted with islets seeded onto Gelitaspon with NGF showed a significant reduction in blood glucose levels by 4 weeks after transplantation, and demonstrated a response similar to non-diabetic mice when tested with an intraperitoneal glucose tolerance test. Chamber tissue from this group contained islets with insulin-producing β cells adjacent to the vascular pedicle. Islets seeded onto Gelitaspon with NGF and sited on femoral vessels using a tissue-engineering chamber offer an alternative method for islet transplantation in diabetic mice. This may have potential as a method for clinical islet transplantation.

Nerve growth factor is associated with islet graft failure following intraportal transplantation

“…Any NGF effect on inter-islet neurovascular enrichment would be more evident when islets are clustered together under the kidney capsule 20 or in biocompatible synthesized chambers. 23 This juxtaposition of islets may also explain the higher efficiency of subcapsular transplants.…”

“…20 Moreover, islets were efficiently transplanted in vascularized chambers based on the neurovascular support from the femoral artery, vein and nerve, in the presence of a gelatin sponge scaffold with NGF. 23 However, the usefulness of NGF in intraportal islet transplantation was still unknown. To resolve this problem, we transplanted syngeneic islets (360 islet equivalents per recipient) cultured with or without 2.5S mouse NGF for 24 h into the portal vein of streptozotocin-induced diabetic BALB/c mice.…”

Neurotrophic Factors and Their Potential Applications in Tissue Regeneration

“…Interestingly, NGF treatment also increases insulin secretion in cultured islet (Rosenbaum et al 2001), as well as in transplanted islet (Miao et al 2005). Injection of 6 μg NGF can restore the glucose tolerance in male Balb/c mice to the level that is comparable to that of islet transplanted mice (Miao et al 2005), or the non-diabetic control mice (Hussey et al 2010). …”

The Use of Biomaterials in Islet Transplantation

“…However, exogenous insulin was still required [82]. A modified approach was taken by Cronin et al [83] in a diabetic mouse model, which involved running a portion of the femoral artery though the lumen of a silicone tube, which was filled with a Matrigel® (BD Biosciences, Franklin Lakes, NJ) solution supplemented with FGF and heparin [84] or Gelita-Spon® (Gelita Medical BV, Amsterdam, Netherlands) supplemented with nerve growth factor (NGF) [85]. In the matrigel study, islets were seeded at the time of implantation or 3 weeks after prevascularization of the chamber.…”

“…Interestingly, the later study demonstrated that prevascularization of the chamber was not required when syngeneic islets were seeded with NGF. In this condition, 80% of mice achieved normoglycemia compared with 0% of mice receiving islets on the gelatin sponge alone [85]. This system takes advantage of an easily vascularized transplantation site, which allows optimal diffusion while eliminating protein deposition and coagulation around the graft.…”