Poster Presentation ASSCR, AGCTS, ISCT ANZ and Friends Joint Scientific Conference 2019

Modelling vascular endothelial cell dysfunction in Friedreich’s ataxia using human iPSCs (#104)

Jarmon G Lees 1 2 , Andrew Treller 2 3 , Anne M Kong 2 , Geraldine Mitchell 2 3 , Mirella Dottori 4 , Alice Pébay 1 , Roger Peverill 5 , Martin Delatycki 6 , Marek Napierala 7 , Arnulf H Koeppen 8 , Penny McKelvie 9 , Shiang Y Lim 1 2
  1. University of Melbourne, Parkville, Victoria, Australia
  2. O’Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
  3. Faculty of Health Sciences, Australian Catholic University, Melbourne, Victoria, Australia
  4. University of Wollongong, Wollongong, NSW, Australia
  5. Monash Cardiovascular Research Centre, Monash Heart and Department of Medicine, Monash University and Monash Health, Clayton, Victoria, Australia
  6. Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
  7. Department of Biochemistry and Molecular Genetics, Stem cell Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA
  8. Departments of Neurology and Pathology, Albany Medical College, Albany, New York, USA
  9. St Vincent’s Hospital, Melbourne, Victoria, Australia

Friedreich ataxia (FRDA) is a hereditary neurodegenerative disorder which is frequently accompanied by cardiomyopathy which can result in premature mortality. Clinical reports have suggested that the associated cardiomyopathy may be linked to abnormalities of the small coronary arteries. This study aims to assess the endothelial and mitochondrial functions in endothelial cells derived from induced pluripotent stem cells derived from FRDA patients (FRDA-iPSCs) and CRISPR-corrected isogenic control iPSCs. Cardiac tissue of FRDA patients displayed focal interstitial fibrosis and increases in endothelial cell proliferation in some small blood vessels, creating a non-uniform intimal layer that partially occluded the vessels. Compared to isogenic controls, FRDA-iPSCs displayed a ~3-fold lower FXN mRNA and ~6-fold lower frataxin protein expression. CD31+ endothelial cells derived from FRDA- and isogenic control-iPSCs expressed endothelial cell markers (CD31 and VE-cadherin) and formed capillary-like tube structures on Matrigel. Compared to isogenic controls, endothelial cells derived from FRDA-iPSCs had higher mitochondrial membrane potential (P<0.05) and equivalent levels of mitochondrial superoxide under basal and oxidative stress conditions. In conclusion, endothelial cells derived from FRDA-iPSCs exhibit abnormal mitochondrial function. This in vitro pre-clinical vascular model may provide a valuable platform for future drug discovery to develop novel treatment for FRDA-induced cardiomyopathy.

  • Have you presented your abstract at another international meeting?: No