Table 1 Studies detailing the generation of FRDA iPSCs and their derived models, as well as their use to investigate FRDA pathology
Study theme | Study | Year | Cell type(s) utilised | Study outcome |
|---|---|---|---|---|
Developing iPSC-derived cellular models of FRDA | Liu et al. [9] | 2011 | FRDA iPSC-derived peripheral neurons FRDA iPSC-derived cardiomyocytes | Successful generation of FRDA iPSCs from patient fibroblasts. These FRDA iPSCs could be differentiated into peripheral neurons and cardiomyocytes |
Wong et al. [11] | 2019 | FRDA iPSC-derived 3D human ventricular cardiomyocyte model | Generation of 3D human-engineered cardiac tissue models from FRDA iPSC-derived cardiomyocytes. These cardiac models show electrophysiological defects and FXN expression-dependent contractility defects | |
Mazzara et al. [12] | 2020 | FRDA iPSC-derived dorsal root ganglia organoid sensory neurons | Generation of a DRG organoid-derived sensory neuronal model from FRDA iPSCs. This model exhibits molecular and cellular phenotypes which are reversed upon excision of the FXN intron 1 | |
Dionisi et al. [13] | 2020 | FRDA iPSC-derived primary proprioceptive neurons | Development of a protocol allowing the successful generation of proprioceptive enhanced cultures (up to 50% of finally differentiated neurons) from FRDA iPSCs. Further cell sorting with FACS resulted in almost pure proprioceptive cultures | |
Investigation of FRDA phenotypic characteristics | Hick et al. [10] | 2013 | FRDA iPSC-derived neurons FRDA iPSC-derived cardiomyocytes | FRDA iPSCs demonstrate expansion instability and reduced FXN expression, but no biological phenotypes. Subsequently derived neurons and cardiomyocytes demonstrate diseased mitochondrial phenotypes |
Lee et al. [14] | 2014 | FRDA iPSC-derived cardiomyocytes | FRDA iPSC-derived cardiomyocytes are similar in size, ATP production rate and calcium handling phenotypes when compared to wild-type controls, despite exhibiting some mitochondrial defects. The presence of an excessive iron supplement resulted in the display of iron-overloading cardiomyopathy phenotypes in the same cells | |
Bird et al. [15] | 2014 | FRDA iPSC-derived neurons | FRDA iPSC-derived neurons possess normal mitochondrial function and show no altered susceptibility to cell death. FRDA iPSC-derived neural progenitors differentiate into functional neurons and following transplantation can successfully integrate in vivo in the cerebellum of adult rodents | |
Crombie et al. [16] | 2015 | FRDA iPSC-derived retinal pigment epithelium cells | Retinal pigment epithelium cells derived from FRDA iPSCs display normal oxidative phosphorylation activity and normal phagocytosis | |
Crombie et al. [17] | 2017 | FRDA iPSC-derived cardiomyocytes | FRDA iPSC-derived cardiomyocytes demonstrate electrophysiological phenotypes of calcium handling deficiency such as increased variation in beating rates (prevented with nifedipine) and low calcium transients | |
Bolotta et al. [18] | 2019 | FRDA iPSC-derived cardiomyocytes | FRDA iPSC-derived cardiomyocytes exhibit increased protein expression of hepcidin and ferroportin and decreased levels of nuclear ferroportin in comparison to controls | |
Investigation into molecular mechanisms underpinning FRDA pathology | Ku et al. [8] | 2010 | FRDA iPSCs | Successful generation of iPSCs from FRDA patient fibroblasts, which maintain FXN gene repression and demonstrate GAA repeat instability. Silencing of MSH2 (which occupies FXN intron 1) impairs the GAA repeat expansion in FRDA iPSCs |
Du et al. [19] | 2012 | FRDA iPSCs FRDA iPSC-derived neural precursors FRDA iPSC-derived neurospheres | Increased expression of MSH2, MSH3 and MSH6 was found in FRDA patient-derived iPSCs, with silencing of MSH2 and MSH6 impairing the repeat expansion. Treatment of FRDA iPSCs with polyamide FA1 partially blocks GAA repeat expansions | |
Eigentler et al. [20] | 2013 | FRDA iPSC-derived peripheral sensory neurons | Successful generation of peripheral sensory neurons and neural crest progenitors from FRDA iPSCs. FRDA iPSCs failed to upregulate frataxin during differentiation to FRDA peripheral sensory neurons | |
Shan et al. [21] | 2014 | FRDA iPSC-derived neural stem cells | Identification of protein targets and mechanistic pathways for an HDAC inhibitor (compound 106) in FRDA iPSC-derived neural stem cells. Targets of compound 106 are likely involved in both transcriptional regulation and post-transcriptional processing of mRNA | |
Igoillo-Esteve et al. [22] | 2015 | FRDA iPSC-derived β cells FRDA iPSC-derived neurons | β cell death due to frataxin deficiency is a consequence of activation of the intrinsic apoptotic pathway, which is activated in FRDA iPSC-derived neurons and β cells. Prevention of the intrinsic apoptotic pathway activation is seen with cAMP induction | |
Rodden et al. [23] | 2021 | FRDA iPSC-derived neurons | Determination of previously unrecognised differentially methylated region upstream of expanded repeat in FRDA iPSC-derived neurons | |
Cotticelli et al. [24] | 2022 | FRDA iPSC-derived cardiomyocytes | Transcriptomic analysis of a novel FRDA iPSC isogenic cardiomyocyte model demonstrated mitochondrial dysfunction and a type 1 interferon activation response as pathways most affected by frataxin deficiency | |
Angulo et al. [25] | 2022 | FRDA iPSC-derived neurons FRDA iPSC-derived cardiomyocytes | Identification of differentially expressed genes in FRDA iPSC-derived neurons and cardiomyocytes demonstrated that glycolysis and extracellular matrix-involved pathways are most affected by FXN deficiency in neurons and cardiomyocytes, respectively |