Endocrine Abstracts

Introduction: One goal of diabetic regenerative medicine is to instructively convert mature pancreatic exocrine cells into insulin-producing cells. We recently reported that liganded thyroid hormone receptor α (TRα) plays a critical role in expansion of the β-cell mass during postnatal development.

Materials and Methods: AdTRα is a recombinant adenoviral vector that expresses human TRα1 under the control of the cytomegalovirus promoter. To analyze whether TRα gene transfer induces reprogramming of pancreatic exocrine cells to insulin-producing cells, AdTRα were injected into the pancreas of immunodeficient mice. Rat pancreatic AR42J cells that possess exocrine and neuroendocrine properties were infected with AdTRα. The expression of transcription factors that are involved in the differentiation of pancreatic endocrine cells was then analyzed by quantitative RT-PCR, western blot or immunocytochemistry. To explore whether liganded-TRα-induced reprogramming of pancreatic exocrine cells is direct or indirect effect, AdTRα-infected AR42J cells were concomitantly transfected with siRNA of Ngn3 or MafA.

Results: Small scattered clusters of insulin-producing cells, which also expressed lipase, were observed in AdTRα-infected mice. T3-treatment of AR42J cells that were infected with AdTRα and pretreated with activin A increased the mRNA and protein expression levels of Ngn3 and MafA, compared to no T3-treatment. Overexpression of TRα together with T3-treatment also induced insulin expression in activin A-treated AR42J cells. The siRNA-induced inhibition of expression of Ngn3 or MafA significantly inhibited AdTRα-induced reprogramming of AR42J cells into insulin-producing cells.

Conclusions: These results suggested that combination of liganded-TRα and activin A leads to reprogramming pancreatic exocrine cells to insulin-producing cells via induction of Ngn3 and MafA. Our findings also support the hypothesis that liganded-TRα plays a critical role in β-cell regeneration during postnatal development.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.