Altered Secretome and ROS Production in Olfactory Mucosa Stem Cells Derived from Friedreich’s Ataxia Patients

Abstract

Friedreich’s ataxia is the most common hereditary ataxia for which there is no cure or approved treatment at present. However, therapeutic developments based on the understanding of pathological mechanisms underlying the disease have advanced considerably, with the implementation of cellular models that mimic the disease playing a crucial role. Human olfactory ecto-mesenchymal stem cells represent a novel model that could prove useful due to their accessibility and neurogenic capacity. Here, we isolated and cultured these stem cells from Friedreich´s ataxia patients and healthy donors, characterizing their phenotype and describing disease-specific features such as reduced cell viability, impaired aconitase activity, increased ROS production and the release of cytokines involved in neuroinflammation. Importantly, we observed a positive effect on patient-derived cells, when frataxin levels were restored, confirming the utility of this in vitro model to study the disease. This model will improve our understanding of Friedreich´s ataxia pathogenesis and will help in developing rationally designed therapeutic strategies.

Loss of filamentous actin, tight junction protein expression, and paracellular barrier integrity in frataxin-deficient human brain microvascular endothelial cells—implications for blood-brain barrier physiology in Friedreich’s ataxia

“…Furthermore, matrix metalloprotease-9 is upregulated in FRDA patient blood samples and the KIKO FRDA mouse model, potentially disrupting the integrity of the vascular basement membrane ( Nachun et al, 2018 ; Zhao et al, 2020 ). Cyclooxygenases are increased in several FRDA mouse models and isolated FRDA patient B-lymphocytes, and VEGF is increased in FRDA patient olfactory mucosal mesenchymal stem cells; both pathways are correlated to downregulation of claudin-5 and occludin, the former protein being the essential claudin isoform in brain vasculature ( Chen et al, 2009 ; Chiu and Lai, 2013 ; Greene et al, 2019 ; Pérez-Luz et al, 2020 ; Zhao et al, 2022 ). Therefore, with all aforementioned clinical and molecular details describing the potential for vascular breakdown, we sought to directly interrogate brain-derived vascular barrier integrity in shFXN hBMVEC.…”

Effect of Mitochondrial and Cytosolic FXN Isoform Expression on Mitochondrial Dynamics and Metabolism

“…Fibroblasts represent a well-established in vitro model for studying FRDA cellular mechanisms [29,30], while olfactory ecto-mesenchymal stem cells (OE-MSCs) are a novel model that has the advantage of being able to be differentiated into several cell types, including neurons [31]. Our lab has extensively worked on the characterization of this cellular model [32]. For this reason, we first transduced OE-MSCs derived from a FRDA patient with the Lv-FXN I (Figure 1A) or the Lv-FXN II (Figure 1B) for 48 h, which allowed us to obtain a frataxin expression level of 200-400% when compared to untreated cells.…”