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Islets and mesenchymal stem cells co-encapsulation can improve subcutaneous bioartificial pancreas survival in diabetic primates

Sophie Veriter¹, Najima Aouassar^1,2, Daela Xhema^1,2, Gwen Beaurin¹, Pierre-Yves Adnet¹, Yasuhiro Igarashi¹, Pierre Gianello¹, Denis Dufrane^1,2

¹Laboratory of Experimental Surgery; ²Endocrine Cell Therapy Unit; UCL - Université Catholique de Louvain, Brussels, Belgium

Objective: Insufficient oxygenation can limit the survival of encapsulated pig islets in the subcutaneous tissue. The transplantation of co-encapsulated pig islets with adipose (AMSCs) or bone marrow mesenchymal stem cells (BM-MSCs) was then investigated to improve implant vascularization, oxygenation and consequently the diabetes correction in primates.

Methods: Co-incubation of AMSCs/BM-MSCs with islets was, firstly, in vitro performed to assess the islets viability/functionality/oxygen consumption (48/72hrs of incubation at 5/20mM glucose).

Secondly, streptozotocin-diabetic primates (fasting blood glucose, FBG>160mg/dl; HbA₁c>13%) were subcutaneously transplanted with porcine islets co-encapsulated with BM-MSCs (n=4) or AMSCs (n=6). Recipients were monitored metabolically FBG/glycated haemoglobin (HbA₁c), body weight) and immunologically (preformed anti-pig antibodies, cytotoxicity and anti-α-Gal response by FACS/ELISA, respectively). The neoangiogenesis, expression of Vascular Endothelial Growth Factor (VEGF) and factor VIII were assessed by histomorphometry on explanted grafts. Results were compared to primates transplanted with encapsulated islets alone (n=5).

Results: AMSCs co-incubated with islets demonstrated, in vitro, a significant better islets survival than islets alone (p<0.05).

A significant lower FBG (at 24 weeks post-transplantation) was found for primates transplanted with co-encapsulated islets/BM-MSCs or AMSCs (76mg/dl) in comparison to encapsulated islets alone (215mg/dl). A significant better correction of HbA1c was also found in primates transplanted with AMSCs or BM-MSCs/islets (HbA1c: 7.8% and 7.3%, respectively,n=4) in contrast to islets alone (10.9%,n=4) at 28 weeks post-transplantation.

A similar increase of cytotoxic IgG anti-Gal antibodies was found for each experimental group. A higher level of VEGF and factor VIII expression was found in the surrounding tissue of co-encapsulated islets/AMSCs in comparison with islets/BM-MSCs and islets alone (p<0.01) associated with a higher number of vessels/area than encapsulated islets alone (p<0.001).

Conclusion: The co-encapsulation of pig islets with MSCs can improve significantly the islets survival in vitro as well as the function and the neoangiogenesis of bioartificial pancreas in a primate preclinical model.