Tissue-specific stem cells obtained by reprogramming of Non-obese diabetic (NOD) mouse-derived pancreatic cells confer insulin production in response to glucose

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Abstract

Type 1 diabetes occurs due to the autoimmune destruction of pancreatic (3-cells in islets. Transplantation of islets is a promising option for the treatment of patients with type 1 diabetes that experience hypoglycemic unawareness despite maximal care, but the present shortage of donor islets hampers such transplantation. Transplantation of insulin-producing cells derived from the patients themselves would be one of the most promising approaches to cure type 1 diabetes. Previously, we demonstrated that insulin-producing cells could be produced by transfecting murine pancreatic cells with Yamanaka's reprogramming factors. Non-obese diabetic (NOD) mice are naturally occurring mutant mice defective in insulin production due to autoimmune ablation of pancreatic (3-cells. In this study, we showed that glucose-sensitive insulin-producing cells are successfully generated by transfecting primary pancreatic cells from NOD mice (aged 6 months old) with a plasmid harboring the cDNAs for Oct-3/4, Sox2, Klf4, and c-Myc. Transfection was repeated 4 times in a 2 dayinterval. Sixty-five days after final transfection, cobblestone-like colonies appeared. They proliferated in vitroand expressed pluripotency-related genes as well as Pdx1, a transcription factor specific to tissue-specific stem cells for the (3-cell lineage. Transplantation of these cells into nude mice failed to produce teratoma unlike induced pluripotent stem cells (iPSCs). Induction of these cells to the pancreatic (3-cell lineage demonstrated their capability to produce insulin in response to glucose. These findings suggest that functional pancreatic (3-cells can be produced from patients with type 1 diabetes. We call these resultant cells as "induced tissue-specific stem cells from the pancreas" (iTS-P) that could be valuable sources of safe and effective materials for cell-based therapy in type 1 diabetes.

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APA

Saitoh, I., Sato, M., Soda, M., Inada, E., Iwase, Y., Murakami, T., … Noguchi, H. (2016). Tissue-specific stem cells obtained by reprogramming of Non-obese diabetic (NOD) mouse-derived pancreatic cells confer insulin production in response to glucose. PLoS ONE, 11(9). https://doi.org/10.1371/journal.pone.0163580

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