4-(5-benzo(1-3)dioxol-5-yl-4-pyridin-2-yl-1h-imidazol-2-yl)benzamide and Diabetes-Mellitus--Type-1

The generation of induced pluripotent stem cells (iPSCs) provides a promising possibility for type 1 diabetes therapy. However, the generation of insulin-producing cells from iPSCs and evaluation of their efficacy and safety should be achieved in large animals before clinically applying iPSC-derived cells in humans. Here we try to generate insulin-producing cells from rhesus monkey (RM) iPSCs.. Based on the knowledge of embryonic pancreatic development, we developed a four-stage protocol to generate insulin-producing cells from RM iPSCs. We established a quantitative method using flow cytometry to analyse the differentiation efficiency. In addition, to evaluate the differentiation competence and function of RM iPSC-derived cells, transplantation of stage 3 and 4 cells into immunodeficient mice was performed.. RM iPSCs were sequentially induced to definitive endoderm (DE), pancreatic progenitors (PP), endocrine precursors (EP) and insulin-producing cells. PDX1(+) PP cells were obtained efficiently from RM iPSCs (over 85% efficiency). The TGF-β inhibitor SB431542 promoted the generation of NGN3(+) EP cells, which can generate insulin-producing cells in vivo upon transplantation. Finally, after this four-stage differentiation in vitro, insulin-producing cells that could secrete insulin in response to glucose stimulation were obtained. When transplanted into mouse models for diabetes, these insulin-producing cells could decrease blood glucose levels in approximately 50% of the mice.. We demonstrate for the first time that RM iPSCs can be differentiated into functional insulin-producing cells, which will provide the basis for investigating the efficacy and safety of autologous iPSC-derived insulin-producing cells in a rhesus monkey model for type 1 diabetes therapy.

Topics: Animals; Benzamides; Cell Differentiation; Cell- and Tissue-Based Therapy; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dioxoles; Disease Models, Animal; Glucose; Induced Pluripotent Stem Cells; Insulin; Insulin-Secreting Cells; Macaca mulatta; Male; Mice; Mice, Inbred NOD; Mice, SCID; Streptozocin; Treatment Outcome