Developing induced pluripotent stem cell derived cardiomyocytes as a model to study Friedreich's ataxia
File(s)
Author(s)
Ellina, Soteroulla
Type
Thesis
Abstract
Friedreich’s Ataxia (FRDA) is a multisystem disorder which mainly affects the proprioceptive
neurons and the heart. Induced pluripotent stem cells (iPSCs) derived from FRDA patients and
healthy individuals were differentiated to cardiomyocytes (CMs)- one of the most affected cell types which were cultured for 22, 30, and 105 days. For the first time, Gene Ontology (GO) analyses
were performed on FRDA-iPSC-cardiomyocytes day 105 (CM-d105). In agreement with other FRDA models, GO analyses have shown defects in mitochondrial adenosine triphosphate (ATP) generation, in inflammatory response and in calcium homeostasis- as also confirmed by calcium handling assays on FRDA-iPSC-cardiomyocytes day 30 (CM-d30). Besides these already known abnormalities, for the first time- morphological immaturity of FRDA-iPSC-CMs is reported. Transcriptomic data acquired from FRDA-iPSC-proprioceptive neurons (PPNs) exhibit a defective neural crest stem cell pathway, similar to FRDA-CM-d105, revealing a commonly affected pathway between the two most susceptible cell types in FRDA. Neural crest stem cells contribute to the formation of both the peripheral nervous
system (PNS) and the heart, and this finding potentially indicates a developmental defect in FRDA. Previously identified biomarkers from FRDA lymphocytes and peripheral blood mononuclear cells (PBMCs) were compared with the FRDA-CM-d105 gene expression. Specific genes including CBS
for monitoring the iron metabolism, PDLIM1, TXNRD2 and BNIP3 for indicating the oxidative
stress status, and finally TBL1X for assessing the genotoxic stress, were similarly affected between the different cell types and can potentially be used as non-invasive markers of the disease progress. Having established that these FRDA-iPSC-CMs recapitulate certain aspects of the disease, the development of a platform consisting of this cell model was initiated to be employed for genetic and drug screening.
neurons and the heart. Induced pluripotent stem cells (iPSCs) derived from FRDA patients and
healthy individuals were differentiated to cardiomyocytes (CMs)- one of the most affected cell types which were cultured for 22, 30, and 105 days. For the first time, Gene Ontology (GO) analyses
were performed on FRDA-iPSC-cardiomyocytes day 105 (CM-d105). In agreement with other FRDA models, GO analyses have shown defects in mitochondrial adenosine triphosphate (ATP) generation, in inflammatory response and in calcium homeostasis- as also confirmed by calcium handling assays on FRDA-iPSC-cardiomyocytes day 30 (CM-d30). Besides these already known abnormalities, for the first time- morphological immaturity of FRDA-iPSC-CMs is reported. Transcriptomic data acquired from FRDA-iPSC-proprioceptive neurons (PPNs) exhibit a defective neural crest stem cell pathway, similar to FRDA-CM-d105, revealing a commonly affected pathway between the two most susceptible cell types in FRDA. Neural crest stem cells contribute to the formation of both the peripheral nervous
system (PNS) and the heart, and this finding potentially indicates a developmental defect in FRDA. Previously identified biomarkers from FRDA lymphocytes and peripheral blood mononuclear cells (PBMCs) were compared with the FRDA-CM-d105 gene expression. Specific genes including CBS
for monitoring the iron metabolism, PDLIM1, TXNRD2 and BNIP3 for indicating the oxidative
stress status, and finally TBL1X for assessing the genotoxic stress, were similarly affected between the different cell types and can potentially be used as non-invasive markers of the disease progress. Having established that these FRDA-iPSC-CMs recapitulate certain aspects of the disease, the development of a platform consisting of this cell model was initiated to be employed for genetic and drug screening.
Version
Open Access
Date Issued
2023-09-18
Date Awarded
01/12/2023
License URL
Advisor
Festenstein, Richard
Sponsor
Rosetrees Trust
Publisher Department
Department of Brain Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)