Thesis defence Loncaric Darija "Attenuation of oxidative phosporylation and induction of hypxic cell response : α-Tocopherol-Acetate and mir-210 effects on mesenchymal stromal cells"

Détails de la réservation

Détails de l'évènement

Loncaric Darija

 

"Attenuation of oxidative phosporylation and induction of hypxic cell response :  α-Tocopherol-Acetate and mir-210 effects on mesenchymal stromal cells"

 


Abstract :

In this thesis, we combined approaches of single-cell cultures, flow-cytometry, energetic metabolism analysis and molecular genetics in order to get insight in the effects of α-Tocopherol-Acetate (α-TOA) on Mesenchymal Stromal Cells (MStroC) and their functional subpopulations (mesenchymal stem and progenitor cells). The other aim was to test a miR-210 molecule with respect to its potential use as hypoxia-mimicking molecule. After defining MStroC population heterogeneity and concluding that the first-passage population is appropriate for further experiments, we demonstrated that α-TOA exhibits a positive effect on the maintenance of high proliferative capacity of mesenchymal stem cells. This effect could be associated with an attenuation of electron transport chain (ETC) activity, which, in turn, could explain the moderate increase in the level of mitochondrial Reactive Oxygen Species (mtROS) we detected. The increase in mtROS level could be associated with a decreased HIF-1 alpha protein degradation in MStroC exposed to α-TOA. Although we did not detect a compensatory increase in glycolysis, the observed phenomena depict part of a complex cellular response to the low O2 that is demonstrated to be related with the maintenance of stem cell primitiveness. The exact mechanism remains to be elucidated as well as its translational potential.
In addition, we provided new evidences that miR-210 is integral part in MStroC response to low O2. In the study, we showed an increased miR-210 expression after short-term (up to 24 hours) or an extended (up to 72 hours) MStroC exposure to low O2. Moreover, we demonstrated that this microRNA (miRNA) could be induced by both HIF-1 and HIF-2 transcriptional factors, suggesting it as integral part of MStroC response to low O2. So far, our data indicates miR-210 to be worthy to consider as a good candidate for hypoxia-mimicking molecule. Additionally, the data we obtained supports progress to next-step project of miR-210 transitory over-expression in MStroC ex vivo cultures with an aim to challenge its potential to support survival and population growth of MStroC in low oxygenated or/and ischemic context.


Keywords: Mesenchymal Stromal Cells, Mesenchymal Stem Cells, α-Tocopherol-Acetate, miR-210, Hypoxia, Metabolism

Responsable

  • Nom : Loncaric Darija