Ligand-bound Thyroid Hormone Receptor Contributes to Reprogramming of Pancreatic Acinar Cells into Insulin-producing Cells

Abstract

Background: One goal of diabetic regenerative medicine is to convert mature pancreatic acinar cells into insulin-producing cells. Results: Ligand-bound thyroid hormone receptor ␣ (TR␣), which interacts with p85␣, induces phosphatidylinositol 3-kinase (PI3K) signaling and insulin expression. Conclusion: PI3K signaling must be activated for TR␣-induced reprogramming of pancreatic acinar cells. Significance: TR␣ is critical for postnatal expansion of the ␤-cell mass.

Impaired Oxidative Endoplasmic Reticulum Stress Response Caused by Deficiency of Thyroid Hormone Receptor α

“…Thyroid hormone effects on glucose homeostasis and on endocrine function of the pancreas are the result of an interaction of the thyroid hormone with its receptors. Recently, we also reported that liganded TR␣ induced expansion of the ␤-cell mass after streptozotocin-induced ␤-cell loss by an increase in the ␤-cell replication and reprogramming of pancreatic acinar cells (12). In this study, long term exposure to oxidative stress enhanced cell death of pancreatic ␤-cells when the expression of endogenous TR␣ was extinguished.…”

“…Analyses of Reactive Oxygen Species (ROS) and ApoptosisBy Ficoll gradient centrifugation, the endocrine fraction was prepared from 4-week-old mice (12). Subsequently, the pancreatic ␤-cells were cultured for 6 h on 35-mm culture dishes with RPMI 1640 Gluta MAX-I medium supplemented with 10% resin-stripped FBS at 37°C under 5% CO 2 atmosphere.…”

Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes Mellitus

“…Dor and co-workers suggested that new β-cells can only be generated from preexisting β-cells instead of MSCs and concluded that MSCs only served as a Btropic mediator^to support islet function in an indirect manner, such as promoting angiogenesis [64]. However, some reports did show that IPCs can be regenerated from the transdifferentiation of other cells, pancreatic duct cells, and acinar cells [65][66][67].…”

Epigenetic-Mediated Reprogramming of Pancreatic Endocrine Cells

“…A recent study exploited the role of ligand-bound thyroid hormone receptor  (TR) in expansion of -cell mass during postnatal development (28). Adenovirus-mediated expression of TR in pancreatic acinar cells activated -cell-specific transcription factors such as Hnf6, Foxa2, Nkx2.2, NeuroD1, Pdx1, Ngn3, and MafA when stimulated by thyroid hormone (28).…”

“…A recent study exploited the role of ligand-bound thyroid hormone receptor  (TR) in expansion of -cell mass during postnatal development (28). Adenovirus-mediated expression of TR in pancreatic acinar cells activated -cell-specific transcription factors such as Hnf6, Foxa2, Nkx2.2, NeuroD1, Pdx1, Ngn3, and MafA when stimulated by thyroid hormone (28). These results suggest that identification of cell-specific markers within the endocrine system may be exploited to modulate gene expression by small-molecule compounds that drive direct reprogramming to insulin producing cells.…”