Adipose derived stem cells (ASC) reduce their adipogenic capacity when they become old, which leads to aging and increase the risk of obesity related diseases. How does the metabolic environment affect the capacity of differentiation of ASC? Our hypothesis is that gerometabolites and APOE affects the production of NAD+/NADH and AMPK activity, in consequence Sirtuin 1 —a deacetylase enzyme related with transcription factors regulation— and the peroxisome proliferator activated receptor gamma —essential for the plasticity and differentiation of mesenchymal stem cell— diminish their actions. The methodological approach of this project bases on two biological models - the New Zealand white APOE-/- rabbit and human mesenchymal stem cell lines from patients. ASCs from the different donors (grouped by age and metabolic status) will be analysed for AMPK-Sirt1-PPARy pathway activation, PPARy modification and adipogenic differentiation capacity.
Alicia Toto Nienguesso (PhD):Metabolic memory of cells as posttranslational modifications (PTMs) - PTMs as key regulators of metabolic ageing in adult stem cells
Our interest focuses on changes in histone modifications of stem cells, which were shown to depend on age and metabolic changes in the cell environment in a previous study. We are investigating the potential molecular mechanisms based on the crosstalk of two important posttranslational modifications - histone methylation and O-GlcNAcylation (addition of N-acetylglucosamine (GlcNac) to serine/threonine residues) of the methylase EZH2. The O-GlcNAcylation of EZH2 at several serine and threonine moieties such as serine 75 seems to be required for EZH2 protein stability in tumor cells and therefore may facilitate the histone H3 trimethylation at K27 to form H3K27me3. Both O-GlcNAcylation and EZH2-mediated H3K27me3 formation play a pivotal role in adipogenic development and stem cell maintenance. Our hypothesis is that specific O‑GlcNAcylation of EZH2 regulates stem cell properties and provides a new mechanism of cellular ageing in embryonic and adult stem cells.