Author:
Wakabayashi Yuka,Miyatsuka Takeshi,Miura Masaki,Himuro Miwa,Taguchi Tomomi,Iida Hitoshi,Nishida Yuya,Fujitani Yoshio,Watada Hirotaka
Abstract
AbstractAs diabetes results from the absolute or relative deficiency of insulin secretion from pancreatic β cells, possible methods to efficiently generate surrogate β cells have attracted a lot of efforts. To date, insulin-producing cells have been generated from various differentiated cell types in the pancreas, such as acinar cells and α cells, by inducing defined transcription factors, such as PDX1 and MAFA, yet it is still challenging as to how surrogate β cells can be efficiently generated for establishing future regenerative therapies for diabetes. In this study, we demonstrated that the exogenous expression of PDX1 activated STAT3 in α cells in vitro, and STAT3-null PDX1-expressing α cells in vivo resulted in efficient induction of α-to-β reprogramming, accompanied by the emergence of α-cell-derived insulin-producing cells with silenced glucagon expression. Whereas β-cell ablation by alloxan administration significantly increased the number of α-cell-derived insulin-producing cells by PDX1, STAT3 suppression resulted in no further increase in β-cell neogenesis after β-cell ablation. Thus, STAT3 modulation and β-cell ablation nonadditively enhance α-to-β reprogramming induced by PDX1, which may lead to the establishment of cell therapies for curing diabetes.
Funder
Ministry of Education, Culture, Sports, Science and Technology
Kanae Foundation for the Promotion of Medical Science
Japan IDDM network
The joint research program of the Institute for Molecular and Cellular Regulation, Gunma University
Japan Society for the Promotion of Science
Publisher
Springer Science and Business Media LLC