Improvement of a subcutaneous bioartificial pancreas : study of different alginate compositions and improvement of islets survival and function
(2012)
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- (en) Despite continuous improvements, islets transplantation as an alternative treatment for type 1 diabetes remains limited by (i) the need of lifelong immunosuppression, associated to numerous side-effects, and (ii) the lack of human pancreas donors. Therefore, (i) we worked in a model of islets encapsulation to protect them against the immune system of the recipient and (ii) we investigated alternative sources of ß-cells. First, in a Wistar rat model, SLM 100 3% v/v, a biocompatible encapsulation material for designing a subcutaneous bioartificial pancreas was selected among six alginates of different chemical compositions. Diabetic state and oxygen consumption by encapsulated islets are associated with insufficient implant oxygenation for optimal islets survival and function (~2% O2 vs. ~5% O2, respectively) and consequently, with early cellular death. The use of mesenchymal stem cells (from bone marrow [BM-MSC] and adipose tissue [AMSC]) was therefore investigated in vitro and in vivo to improve early implant vascularization and oxygenation in diabetic rats and primates. Higher oxygen levels were found in subcutaneous implants containing AMSCs in comparison with encapsulated BM-MSCs or empty implants (~4.4 vs. ~2.6% O2, respectively). Improved graft vascularization was found at short (4 weeks) and long term (8-32 weeks) in vivo in diabetic rats and primates. Diabetic primates transplanted with islets + MSCs demonstrated better graft function and survival in comparison to islets alone (glycated hemoglobin of 7.8% vs. 10.9% at 28 weeks post-transplantation; maximal graft function of 32 weeks vs. 28 weeks, respectively). The use of pig islets as an alternative source of human islets is limited by their low insulin response after glucose challenge (stimulation index of ~2 vs. 12 for pig vs. human, respectively) due to a major difference in β- and α-cell composition in islets. Therefore, a method for the in vivo pig islet structure remodeling was developed. Treatment of pigs with low doses of streptozotocin (30 and 50 mg/kg) showed optimal structure remodeling, with an increased proportion of α-cells per islet (+300%) without β-cell dysfunction. After in vitro stimulation, these islets demonstrated improved function.
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Vériter, S. (2012). Improvement of a subcutaneous bioartificial pancreas : study of different alginate compositions and improvement of islets survival and function. https://hdl.handle.net/2078.5/80025