As diabetes mellitus results from the absolute or relative deficiency of insulin secretion from pancreatic β cells, the generation of surrogate β cells has attracted a lot of attention for the cure of diabetes. To date, insulin-producing cells have been generated from differentiated cell types in the pancreas, such as acinar cells and α cells, by inducing the exogenous expression of pancreas-specific transcription factors. However, it still remains unclear as to how surrogate β cells can be efficiently generated toward establishing future regenerative therapies for diabetes. STAT3 has been demonstrated to play a role in maintaining cellular identities in the pancreas, and we have reported that the activation of STAT3 signaling is required for acinar-to-ductal transition (Miyatsuka et al. Genes Dev. 2006), whereas the suppression of STAT3 signaling efficiently promotes acinar-to-β reprogramming (Miura M. et al. EBioMedicine. 2018). Therefore, we hypothesized that regulating STAT3 signaling may control the efficiency of α-to-β reprogramming. To address this, we generated transgenic mice that exogenously express Pdx1, Mafa and Ngn3 specifically in α cells, and deleted Stat3 in a tamoxifen inducible manner (Stat3KO; Gcg-CreERT2; Pdx1;Ngn3;Mafa mice: αStat3KO;PNM mice). Immunofluorescent imaging demonstrated that Stat3 deletion significantly increased the number of α-cell-derived insulin-producing cells in αStat3KO;PNM mice, compared with control mice (28.2±2.7 vs. 8.6±3.1%, p<0.05). Notably, 61.2±8.8% of α-cell-derived insulin-producing cells were negative for glucagon in αStat3KO;PNM mice, which was higher compared with controls (36.4±18.0 %). These results suggest that the suppression of STAT3 signaling efficiently promotes α-to-β reprogramming as well as acinar-to-β reprogramming in mice.

Disclosure

Y. Wakabayashi: None. T. Miyatsuka: None. L. Suzuki: None. M. Himuro: None. T. Katahira: None. M. Miura: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.

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