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Mouse Embryonic Fibroblasts Acquire Sarcomagenesis Potential after Differentiating into Insulin-Producing Cells

Gupta A, Kurtovic S, Ng TT, Tsuyoshi T, Narwani K, Biancotti JC, Spurka L, Funari V, Balzer B, Talavera-Adame D and Dafoe DC

An abundant source of insulin-producing cells would enhance the success of islet transplantation for treatment of diabetes. Insulin-producing cells can be derived from human fibroblasts which acquired a mesenchymal stem cell (MSC) phenotype. However, these MSCs are able to give rise sarcomas after transformation. Our aim was to investigate whether mouse embryonic fibroblast (MEF) acquire sarcomagenesis potential after differentiating to insulinproducing cells. We derived insulin-producing cells from a MEF cell line MMMbz. After differentiation, the cells were labeled with green fluorescent protein (GFP) driven by rat insulin promoter (INS-GFP) for cell isolation, expansion and characterization by immunocytochemistry (ICC), quantitative RT-PCR (qRT-PCR), and genetic microarrays. These cells were then FACS sorted and transplanted under the kidney capsule of SCID mice to evaluate cell behavior. Grafted cells were analyzed by IHC. MMMbz expressed platelet-derived growth factor receptor alpha (PDGFR-α) and nestin. After differentiation, higher expression of beta-cell markers were found in sorted cells compared to non-sorted cells. Genetic microarray corroborated the expression of pancreatic and mesenchymal markers along with activation of cancer pathways. Within 30 days after transplantation, all grafted mice developed undifferentiated sarcomas that impaired further assessments of insulin-producing cell function. Therefore, insulin-producing cell lines can be derived in vitro from mouse embryonic fibroblasts that behave as MSCs but sarcomagenesis potential may be conferred by a subpopulation of transformed cells.