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A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells.

ABSTRACT: 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.

SUBMITTER: Shamsi F

PROVIDER: S-EPMC4614696 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells.

Shamsi Farnaz F Parlato Rosanna R Collombat Patrick P Mansouri Ahmed A

Cell cycle (Georgetown, Tex.) 20140101 24

The putative induction of adult β-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 β-cell ablation mouse model, in which the β-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the β-cell specific genetic ablation of the transcription initiation factor 1A, ...[more]

PMID: 25558832

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Project description:Expansion of beta cells from the limited number of adult human islet donors is an attractive prospect for increasing cell availability for cell therapy of diabetes. However, attempts at expanding human islet cells in tissue culture result in loss of beta-cell phenotype. Using a lineage-tracing approach we provided evidence for massive proliferation of beta-cell-derived (BCD) cells within these cultures. Expansion involves dedifferentiation resembling epithelial-mesenchymal transition (EMT). Epigenetic analyses indicate that key beta-cell genes maintain open chromatin structure in expanded BCD cells, although they are not transcribed. Here we investigated whether BCD cells can be redifferentiated into beta-like cells.Redifferentiation conditions were screened by following activation of an insulin-DsRed2 reporter gene. Redifferentiated cells were characterized for gene expression, insulin content and secretion assays, and presence of secretory vesicles by electron microscopy. BCD cells were induced to redifferentiate by a combination of soluble factors. The redifferentiated cells expressed beta-cell genes, stored insulin in typical secretory vesicles, and released it in response to glucose. The redifferentiation process involved mesenchymal-epithelial transition, as judged by changes in gene expression. Moreover, inhibition of the EMT effector SLUG (SNAI2) using shRNA resulted in stimulation of redifferentiation. Lineage-traced cells also gave rise at a low rate to cells expressing other islet hormones, suggesting transition of BCD cells through an islet progenitor-like stage during redifferentiation.These findings demonstrate for the first time that expanded dedifferentiated beta cells can be induced to redifferentiate in culture. The findings suggest that ex-vivo expansion of adult human islet cells is a promising approach for generation of insulin-producing cells for transplantation, as well as basic research, toxicology studies, and drug screening.

Dataset Information

A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells.

Publications

A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells.

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