Abstract
Dramatic advances in recent decades in understanding the genetics of Friedreich ataxia (FRDA)—a GAA triplet expansion causing greatly reduced expression of the mitochondrial protein frataxin—have thus far yielded no therapeutic dividend, since there remain no effective treatments that prevent or even slow the inevitable progressive disability in affected individuals. Clinical interventions that restore frataxin expression are attractive therapeutic approaches, as, in theory, it may be possible to re-establish normal function in frataxin deficient cells if frataxin levels are increased above a specific threshold. With this in mind several drugs and cytokines have been tested for their ability to increase frataxin levels. Cell transplantation strategies may provide an alternative approach to this therapeutic aim, and may also offer more widespread cellular protective roles in FRDA. Here we show a direct link between frataxin expression in fibroblasts derived from FRDA patients with both decreased expression of hydrogen peroxide scavenging enzymes and increased sensitivity to hydrogen peroxide-mediated toxicity. We demonstrate that normal human mesenchymal stem cells (MSCs) induce both an increase in frataxin gene and protein expression in FRDA fibroblasts via secretion of soluble factors. Finally, we show that exposure to factors produced by human MSCs increases resistance to hydrogen peroxide-mediated toxicity in FRDA fibroblasts through, at least in part, restoring the expression of the hydrogen peroxide scavenging enzymes catalase and glutathione peroxidase 1. These findings suggest, for the first time, that stem cells may increase frataxin levels in FRDA and transplantation of MSCs may offer an effective treatment for these patients.
Highlights
Friedreich ataxia (FRDA) is the commonest autosomal recessive ataxic condition, affecting around 1 in 50,000 of the population [1]
To investigate the effects mesenchymal stem cells (MSCs) have on frataxin expression in fibroblasts derived from patients with FRDA, patient fibroblasts were exposed to MSC conditioned medium in vitro and frataxin expression investigated using western blotting and RT-Polymerase Chain Reaction (PCR) techniques
Frataxin expression in human fibroblasts derived from Friedreich ataxia and healthy control patients
Summary
Friedreich ataxia (FRDA) is the commonest autosomal recessive ataxic condition, affecting around 1 in 50,000 of the population [1]. Major therapeutic strategies in FRDA include development of agents to protect against oxidative damage and mitochondrial respiratory chain defects or agents that increase cellular frataxin expression, since cells lacking frataxin can be rescued through frataxin expression [8]. A large body of research suggests that transplantation of mesenchymal stem cells (MSCs) has therapeutic potential for neurodegenerative disorders through a multitude of different mechanisms These include replacement of lost cells by differentiation into functional tissue, modulation of the immune system to prevent further degeneration, and/or provision of trophic support for the diseased cellular system [15]. Increasing evidence suggests that the major mechanistic protective role of MSCs is their capacity to promote an environment conducive to cellular protection and to support cell survival through the secretion of a diverse range of potentially protective factors, including those with anti-oxidant properties [15,16,17,18,19,20]
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