T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells.
Cristina Aguayo-MazzucatoTerence B LeeMichelle MatzkoAmanda DiIennoHabib RezanejadPreeti RamadossThomas ScanlanAnn Marie ZavackiP Reed LarsenAnthony HollenbergClark ColtonArun SharmaSusan Bonner-WeirPublished in: Diabetes (2018)
Previously, we showed that thyroid hormone (TH) triiodothyronine (T3) enhanced β-cell functional maturation through induction of Mafa High levels of T3 have been linked to decreased life span in mammals and low levels to lengthened life span, suggesting a relationship between TH and aging. Here, we show that T3 increased p16Ink4a (a β-cell senescence marker and effector) mRNA in rodent and human β-cells. The kinetics of Mafa and p16Ink4a induction suggested both genes as targets of TH via TH receptors (THRs) binding to specific response elements. Using specific agonists CO23 and GC1, we showed that p16Ink4a expression was controlled by THRA and Mafa by THRB. Using chromatin immunoprecipitation and a transient transfection yielding biotinylated THRB1 or THRA isoforms to achieve specificity, we determined that THRA isoform bound to p16Ink4a , whereas THRB1 bound to Mafa but not to p16Ink4a On a cellular level, T3 treatment accelerated cell senescence as shown by increased number of β-cells with acidic β-galactosidase activity. Our data show that T3 can simultaneously induce both maturation (Mafa) and aging (p16Ink4a ) effectors and that these dichotomous effects are mediated through different THR isoforms. These findings may be important for further improving stem cell differentiation protocols to produce functional β-cells for replacement therapies in diabetes.
Keyphrases
- induced apoptosis
- cell cycle arrest
- single cell
- dna damage
- type diabetes
- gene expression
- endoplasmic reticulum stress
- genome wide
- endothelial cells
- stem cells
- poor prognosis
- signaling pathway
- dna methylation
- oxidative stress
- adipose tissue
- ionic liquid
- metabolic syndrome
- cell proliferation
- machine learning
- immune response
- skeletal muscle
- data analysis
- blood brain barrier
- mass spectrometry
- type iii
- simultaneous determination
- cerebral ischemia
- solid phase extraction