Department of Surgery
Medical School of Geneva
Human mesenchymal stromal cells improve survival and function of pancreatic iIslets by cell-to-cell contact through N-cadherin
Elisa Montanari1, Redouan Mahou1,2, Solène Passemard2, François Noverraz2, Philippe Morel1, Raphael Meier1, Domenico Bosco1, Jörg D. Seebach3, Christine Wandrey2, Sandrine Gerber-Lemaire2, Carmen Gonelle-Gispert1, Leo H. Buhler1.
1Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland; 2Institut d'Ingénierie Biologique et Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 3Division of Immunology and Allergy, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
Background and Aim: The aim of this study was to evaluate the survival and function of human pancreatic islets co-encapsulated with human Mesenchymal Stromal Cells (MSC) both in vitro and in vivo after transplantation in diabetic mice.
Methods: Human MSC and islets (or pseudo-islets, obtained after digestion and reaggregation of islet cells) were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice. Islet function was evaluated by intraperitoneal glucose tolerance test (IPGTT). Grafts were retrieved after 15 days for morphological analysis. Cell function was tested in vitro by static incubation for islets or pseudo-islets alone and together with MSC. Anti-N-cadherin antibody was added on islets alone or together with MSC for 24h and in vitro insulin secretion was tested by static incubation.
Results: Encapsulated islets alone reversed diabetes in mice after intra-peritoneal transplantation after 2 days and allowed to maintain normoglycemia up to 70 days, compared to free islets, that were rejected in 6±1 days (p<0.0001, Mantel Cox). Transplantation of co-encapsulated islets and MSC maintained normoglycemia in mice up to 90 days (p<0.05, Mantel Cox). IPGTT was performed at day 15 and mice transplanted with combined MSC-islets showed an improved glycemic response compared to mice with islets alone (p<0.001). Graft histology showed MSC located within and around the islets (or pseudo-islets), serving as stromal structure. In vitro, insulin secretion was significantly improved when MSC were in cell-cell contact with islets (or pseudo-islets) compared to islets that were only in paracrine exchange with MSC (co-culture in dual chambers, p<0.05). When N-cadherin was blocked, glucose-induced insulin secretion was decreased in islets cocultured with MSC and not affected in islets incubated alone.
Conclusions: The adhesion molecule N-cadherin is essential for MSC and islets cell-to-cell contact to improve function and survival of islets of Langerhans.
15:30 - 17:00
|Modifying Islet Immunity - Adaptive, Innate, and Xenoimmunity||Human mesenchymal stromal cells improve survival and function of pancreatic iIslets by cell-to-cell contact through N-cadherin||Plenary Room 1|