首页|Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet β cells in various mouse models of diabetes with distinct age of initiation
Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet β cells in various mouse models of diabetes with distinct age of initiation
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维普
During the pathogenesis of type 1 diabetes(T1D)and type 2 diabetes(T2D),pancreatic islets,especially the β cells,face significant challenges.These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin,but the exact mechanism needs to be defined.High-fat diet(HFD)and streptozotocin(STZ)treatment are well-established models to study islet damage in T2D and T1D respectively.Therefore,we applied these two diabetic mouse models,triggered at different ages,to pursue the cell fate transition of isletβ cells.Cre-LoxP systems were used to generate islet cell type-specific(a,β,or δ)green fluorescent protein(GFP)-labeled mice for genetic lineage tracing,thereinto β-cell GFP-Iabeled mice were tamoxifen induced.Single-cell RNA sequencing(scRNA-seq)was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled β cells in STZ-treated mice.STZ-induced diabetes caused extensive dedifferentiation of β cells and some of which transdifferentiated into α or δ cells in both youth-and adulthood-initiated mice while this phenomenon was barely observed in HFD models.β cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells,in contrast,α or δ cells were induced to transdifferentiate into β cells in STZ-treated mice(both youth-and adulthood-initiated).In addition to the re-dedifferentiation of β cells,it is also highly likely that these"α or δ"cells transdifferentiated from pre-existing β cells could also re-trans-differentiate into insulin-producing β cells and be beneficial to islet recovery.The analysis of ScRNA-seq revealed that several pathways including mitochondrial function,chromatin modification,and remodeling are crucial in the dynamic transition of β cells.Our findings shed light on how islet β cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.
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维普
