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Pancreatic islets–derived Mesenchymal stromal cells can enter the pancreatic endocrine commitment but do not achieve consistent maturation

Giacomo Lanzoni^1,2, Roberta Costa¹, Francesco Alviano¹, Cosetta Marchionni¹, Giuseppe Cavallari³, Laura Foroni⁴, Gianandrea Pasquinelli⁵, Roberto Rimondini⁶, Laura Bonsi¹, Riccardo Casadei³, Francesco Minni³, Camillo Ricordi², Luca Inverardi², Gian Paolo Bagnara¹

Departments of ¹Histology, Embryology and Applied Biology, ⁴Specialistic Surgical and Anaesthesiological Sciences, ⁶Pharmacology, University of Bologna, Bologna, Italy; ²Diabetes Research Institute, University of Miami, Miami, FL, United States; Departments of ³General Surgery and Transplantation, ⁵Hematology, Oncology, and Clinical Pathology, Division of Surgical Pathology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

Mesenchymal Stromal Cells (MSC) can be derived from various organs, display a wide differentiation potential and appear to have trophic effects. They have been shown to promote islet survival and function and are thus attractive for diabetes treatments that may include composite transplants. Furthermore, MSC have been shown to give rise to islet cell-like clusters. Pancreatic islet-derived mesenchymal stromal cells (PI-MSC) may be more prone to commit to islet specific phenotypes due to their tissue derivation.

We isolated and expanded MSC from human pancreatic islets. Cell populations were characterized by flow cytometry and immunofluorescence. The differentiation potential toward mesenchymal and pancreatic endocrine cells was tested in vitro and in vivo after transplantation in streptozotocin-induced diabetic rats.

After expansion in Chang medium, pancreatic islet-derived stromal cells expressed MSCs markers: CD44+, CD73+, CD90+, CD105+, CD146 low+, CD14-, CD19-, CD34-, CD45-, HLA-DR-. The cells showed multidifferentiation potential toward adipocytes and endothelial cells; moreover, they differentiated towards endocrine lineages both in vitro and in vivo, increasing insulin levels and, to a higher extent, glucagon levels. Under our induction conditions, PI-MSC gave rise to cells with a mixed phenotype and incomplete differentiation. After transplantation in diabetic rats, a transient effect was evidenced by a lowering of glycemia levels and of water intake. Two weeks after xenotransplantation in the absence of immune suppression, glucagon- and insulin-expressing cells were detected in grafts. Cells coexpressing the pericytic marker CD146 and endocrine markers were observed.

PI-MSC seem to have the potential to enter the pancreatic endocrine commitment resulting in in vivo amelioration of blood glucose control in transplanted animals. Improvements in expansion and differentiation protocols will result in additional efficacy.