STAT3 suppression and β-cell ablation enhance α-to-β reprogramming mediated by Pdx1

Abstract

As 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.

Gene expression analysis reveals diabetes-related gene signatures

“…Lastly, STAT3 expression has been associated with β-cell dysfunction and promotion of neonatal diabetes [ 72 ]. Moreover, STAT3 has been suggested to play a role in regulating cellular plasticity and in α- to β-cell transdifferentiation [ 73 ].…”

Lateral hypothalamic GABAergic neurons encode alcohol memories

“…Finally, although our findings show a specific role in cue-alcohol reward learning of the subpopulation of LH neurons defined by GAD expression, these are a heterogeneous population of neurons. This viral targeting strategy we used has been used in previous studies to restrict viral-mediated gene expression in GABAergic neurons in ventral tegmental area 29,36 . In LH, there is evidence from single-cell transcriptomics 37 that GAD mRNA is expressed in all vGat (Slc32a1 mRNA) neurons, however this study also shows co- expression in glutamatergic neurons (Slc17a6 mRNA) in 4 of the 15 clusters they identified.…”