Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA.

ABSTRACT: Specification and maturation of insulin(+) cells accompanies a transition in expression of Maf family of transcription factors. In development, MafA is expressed after specification of insulin(+) cells that are expressing another Maf factor, MafB; after birth, these insulin(+) MafA(+) cells stop MafB expression and gain glucose responsiveness. Current differentiation protocols for deriving insulin-producing ?-cells from stem cells result in ?-cells lacking both MafA expression and glucose-stimulated insulin secretion. So driving expression of MafA, a ?-cell maturation factor in endocrine precursors could potentially generate glucose-responsive MafA(+) ? cells. Using inducible transgenic mice, we characterized the final stages of ?-cell differentiation and maturation with MafA pause/release experiments. We found that forcing MafA transgene expression, out of its normal developmental context, in Ngn3(+) endocrine progenitors blocked endocrine differentiation and prevented the formation of hormone(+) cells. However, this arrest was reversible such that with stopping the transgene expression, the cells resumed their differentiation to hormone(+) cells, including ?-cells, indicating that the block likely occurred after progenitors had committed to a specific hormonal fate. Interestingly, this delayed resumption of endocrine differentiation resulted in a greater proportion of immature insulin(+)MafB(+) cells at P5, demonstrating that during maturation the inhibition of MafB in ?-cell transitioning from insulin(+)MafB(+) to insulin(+)MafB(-) stage is regulated by cell-autonomous mechanisms. These results demonstrate the importance of proper context of initiating MafA expression on the endocrine differentiation and suggest that generating mature Insulin(+)MafA(+) ?-cells will require the induction of MafA in a narrow temporal window to achieve normal endocrine differentiation.

SUBMITTER: He KH 

PROVIDER: S-EPMC3918466 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature