Patient-specific iPSC-derived cardiac microtissues capture early molecular and cellular changes in Friedreich’s Ataxia cardiomyopathy

Friedreich’s ataxia (FRDA) is a rare familial multisystemic disorder caused by GAA triplet expansions in the frataxin (FXN) gene, leading to gene silencing and reduced FXN protein levels. The nervous system and the heart are the most affected tissues, but cardiomyopathy is the main cause of death. To investigate the molecular and cellular mechanisms underlying FRDA-associated cardiac dysfunction, we built three-dimensional (3D) and tri-cellular cardiac microtissues using FRDA and wild-type control human induced pluripotent stem cells (hiPSCs). Cardiac microtissues containing FRDA hiPSC-derived cardiomyocytes had fragmented mitochondria with enlarged cristae and reduced energetic capacity. FRDA microtissues also had wider intercalated discs and abnormal expression and organisation of cytoskeletal proteins compared with the wild-type microtissues, while contraction properties were overall unchanged. Transcriptional analysis by RNA-seq identified a strong pro-fibrotic and pro-angiogenic signature in microtissue containing FRDA cardiomyocytes, even in the presence of wild-type cardiac fibroblasts and endothelial cells. This suggested that FRDA cardiomyocytes are active contributors to the observed phenotypes. The inclusion of FRDA cardiac fibroblasts and endothelial cells in the microtissues confirmed pro-fibrotic remodelling. Altogether, our work captured early molecular changes in FRDA microtissues, providing valuable insights into the pathogenesis of FRDA cardiomyopathy. Our model can be exploited in future for drug screening and for testing treatments that can ameliorate the observed FRDA cardiomyopathy-related phenotypes.