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Beta-cell regeneration from vimentin+/MafB+ cells after STZ-induced extreme beta-cell ablation.

ABSTRACT: Loss of functional beta-cells is fundamental in both type 1 and type 2 diabetes. In situ beta-cell regeneration therefore has garnered great interest as an approach to diabetes therapy. Here, after elimination of pre-existing beta cells by a single high-dose of streptozotocin (STZ), we demonstrated that a considerable amount of beta-like-cells was generated within 48 hrs. But the newly formed insulin producing cells failed to respond to glucose challenge at this time and diminished afterwards. Insulin treatment to normalize the glucose level protected the neogenic beta-like cells and the islet function was also gradually matured. Strikingly, intermediate cells lacking epithelial marker E-cadherin but expressing mesenchymal cell-specific marker vimentin appeared within 16 hrs following STZ exposure, which served as the major source of insulin-producing cells observed at 24 hrs. Moreover, these intermediate cells strongly expressed alpha-cell-specific marker MafB. In summary, the data presented here identified a novel intermediate cell type as beta-cell progenitors, showing mesenchymal cell feature as well as alpha-cell marker MafB. Our results might have important implications for efforts to stimulate beta-cell regeneration.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC4486952 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Lentinan protects pancreatic β cells from STZ-induced damage.

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Project description:The putative induction of adult ?-cell regeneration represents a promising approach for the treatment of type 1 diabetes. Toward this ultimate goal, it is essential to develop an inducible model mimicking the long-lasting disease progression. In the current study, we have established a novel ?-cell ablation mouse model, in which the ?-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the ?-cell specific genetic ablation of the transcription initiation factor 1A, TIF-IA, essential for RNA Polymerase I activity (TIF-IA(?/?)). Using this approach, we induced a slow apoptotic response that eventually leads to a protracted ?-cell death. In this model, we observed ?-cell regeneration that resulted in a complete recovery of the ?-cell mass and normoglycemia. In addition, we showed that adaptive proliferation of remaining ?-cells is the prominent mechanism acting to compensate for the massive ?-cell loss in young but also aged mice. Interestingly, at any age, we also detected ?-like cells expressing the glucagon hormone, suggesting a transition between ?- and ?-cell identities or vice versa. Taken together, the TIF-IA(?/?) mouse model can be used to investigate the potential therapeutic approaches for type 1 diabetes targeting ?-cell regeneration.

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