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Title: Substrate metabolism and cardiomyogenic differentiation of cardiac progenitor cells
Author: Pakzad, Khadijeh
ISNI:       0000 0004 6346 4873
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Despite being resident in the heart, which derives most its energy needs from the oxidation of fatty acids, cardiac stem/progenitor cells are assumed to be glycolytic. Therefore, the transition of these non-contractile progenitor cells into beating cardiomyocytes necessitates an obligatory transformation of the metabolic infrastructure with mitochondrial network expansion and a distinctive switch from glycolysis to oxidative phosphorylation. However, expansion of progenitor cells in culture may impair their ability to upregulate fatty acid metabolism and increase mitochondrial function. Therefore, the main objective of this project was to determine, for the first time, substrate and energy metabolism in cardiac stem/progenitor cells before, during and after cardiomyogenic differentiation. Control passage two cardiosphere-derived cells (P2-CDCs), created through culture on fibronectin/poly-D-lysine (FN/PDL) or collagen IV/hanging drops (ColIV/HD), have been shown to derive most of their energy needs from glycolysis with elevated lactate efflux. However, after 3-weeks of treatment with 5-Azacytidine (5-Aza) and ascorbic acid (AA), differentiated cells started to upregulate fatty acid oxidation and significantly reduced glycolytic flux and lactate production. Therefore, different metabolic mediators were used to stimulate fatty acid oxidation in differentiated cells. Various media with or without synthetic small molecule(s) were tested to optimize differentiation capacity and to stimulate aerobic oxidative phosphorylation in P2-CDCs. WY-14643+TGFβ supplemented medium was able to induce cardiomyogenic differentiation of P2-CDCs into mature, differentiated myocytes. The differentiated cells showed a significant increase in expression of both cardiac-specific genes and proteins, calcium handling genes as well as transforming glycolytic metabolism into more efficiently producing higher energy system, fatty acid, and carbohydrate oxidation in addition to glycolysis, suggesting they may be forming ventricular myocytes.
Supervisor: Carr, Carolyn ; Clarke, Kieran ; Russel, Angela Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available