Suppression of STAT3 Signaling Promotes Acinar-to-ß Reprogramming Induced by Distinct Transcription Factors
Authors: MIURA MASAKI , MIYATSUKA TAKESHI , SASAKI SHUGO , KATAHIRA TAKEHIRO , SUZUKI LUKA , HIMURO MIWA , NISHIDA YUYA , FUJITANI YOSHIO , MATSUOKA TAKAAKI , WATADA HIROTAKA 
Published: June 2018

Aims: Uncovering pancreas development has helped us to explore efficient methods to generate surrogate β cells to cure diabetes. Since it has been demonstrated that Stat3 plays a role in the plasticity of pancreatic acinar cells (Miyatsuka et al. Genes Dev. 2006), we investigated the possibility that Stat3 signaling affects the cellular reprogramming of pancreatic cells into β cells in vitro and in vivo.

Methods: The combined expression of the defined transcription factors Pdx1, Neurog3, and Mafa was induced in the pancreatic progenitor-like mPAC cells in vitro and in the mouse models in vivo, and Stat3 signaling was modified using Stat3 inhibitors, adenoviruses expressing dominant negative or constitutively active form of Stat3, and Stat3-deleted mice.

Results: Whereas phosphorylation of Stat3 (pStat3) was induced by adenoviral vectors expressing Pdx1 or Mafa, most of the reprogrammed β cells induced by a polycistronic adenoviral vector carrying Pdx1-Neurog3-Mafa cassette (Ad-PNM) were negative for pStat3. On the other hand, suppression of pStat3, using Stat3 inhibitor BP-1-102 or dominant-negative form of Stat3, significantly enhanced β-cell neogenesis by Ad-PNM, whereas a constitutively active form of Stat3 decreased the reprogramming efficiency into β cells. In order to confirm the role of Stat3 in vivo, we generated a transgenic mouse line “acinar-PNM”, which ectopically expressed Pdx1, Neuro3, and Mafa in acinar cells, and found that Stat3 deletion significantly increased the number of newly differentiated β cells in acinar-PNM mice. Furthermore, Stat3 inhibition by BP-1-102 in vivo efficiently induced β-cell neogenesis by Ad-PNM and ameliorated hyperglycemia in alloxan-induced diabetic mice.

Conclusions: Stat3 signaling is suppressed in newly-generated β cells induced by distinct transcription factors, and Stat3 inhibition promotes the reprogramming efficiency into β cells, which could lead to future cell therapy for cure of diabetes.

Disclosure

M. Miura: Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi K.K.. Research Support; Self; Kowa Pharmaceuticals America, Inc. T. Miyatsuka: Research Support; Self; Eli Lilly and Company, Japan Society for the Promotion of Science, Daiichi Sankyo Company, Limited, Novartis Pharma K.K., Astellas Pharma Inc., MSD K.K., Takeda Pharmaceutical Company Limited.. S. Sasaki: None. T. Katahira: None. L. Suzuki: None. M. Himuro: None. Y. Nishida: Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, AstraZeneca. Y. Fujitani: None. T. Matsuoka: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.