Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factorsResearch in context
Masaki Miura,
Takeshi Miyatsuka,
Takehiro Katahira,
Shugo Sasaki,
Luka Suzuki,
Miwa Himuro,
Yuya Nishida,
Yoshio Fujitani,
Taka-aki Matsuoka,
Hirotaka Watada
Affiliations
Masaki Miura
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Takeshi Miyatsuka
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan; Corresponding authors at: Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Takehiro Katahira
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Shugo Sasaki
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Luka Suzuki
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Miwa Himuro
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Yuya Nishida
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Yoshio Fujitani
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Japan
Taka-aki Matsuoka
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; Corresponding authors at: Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Hirotaka Watada
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Background: STAT3 has been demonstrated to play a role in maintaining cellular identities in the pancreas, whereas an activating STAT3 mutation has been linked to impaired β-cell function. Methods: The role of STAT3 in β-cell neogenesis, induced by the exogenous expression of Pdx1, Neurog3, and Mafa, was analyzed in vitro and in vivo. Findings: The expression of phosphorylated STAT3 (pSTAT3) was induced in both Pdx1-expressing and Mafa-expressing cells, but most of the induced β cells were negative for pSTAT3. The suppression of STAT3 signaling, together with exogenously expressed Pdx1, Neurog3, and Mafa, significantly increased the number of reprogrammed β cells in vitro and in vivo, enhanced the formation of islet-like clusters in mice, and ameliorated hyperglycemia in diabetic mice. Interpretation: These findings suggest that STAT3 inhibition promotes cellular reprogramming into β-like cells, orchestrated by defined transcription factors, which may lead to the establishment of cell therapies for curing diabetes. Fund: JSPS, MEXT, Takeda Science Foundation, Suzuken Memorial Foundation, Astellas Foundation for Research on Metabolic Disorders, Novo Nordisk, Eli Lilly, MSD, Life Scan, Novartis, and Takeda.
