Variables that influence transcription factor-mediated acinar to beta cell reprogramming

Abstract

Reprogramming of pancreatic cells into new beta-like cells is a potential therapy for Type 1 diabetes. Pancreatic acinar cells are an appealing target for cellular reprogramming since they are abundant, derived from a common progenitor cell during pancreatic organogenesis, and exhibit significant transcriptional plasticity. Towards this end, it has been reported that adenoviral-mediated expression of three pancreas-specific transcription factors MafA, Pdx1 and Neurog3 (3TF) in immunocompromised Rag1-/- mice resulted in the conversion of pancreatic acinar cells into new, insulin-secreting, beta-like cells. Using a transgenic mouse model to express 3TF in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to beta-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new beta-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new beta-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.