Mesenchymal Stem Cells Restore Frataxin Expression and Increase Hydrogen Peroxide Scavenging Enzymes in Friedreich Ataxia Fibroblasts

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.

Human Adipose Stem Cell–Conditioned Medium Increases Survival of Friedreich's Ataxia Cells Submitted to Oxidative Stress

“…n = 4 in all cases. Color images available online at www.liebertpub.com/scd conditioned medium from healthy patients had similar effects on fibroblasts isolated from FA patients as those observed in this work [29]. Our work elucidates on the possible mechanisms by which the conditioned medium induces the increase in cell survival as well as frataxin upregulation.…”

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

“…In particular, FXN overexpression enhances Gpx1 activity, increases cellular glutathione content, and upregulates Cat, at least in vitro. 4,15,28,32 In our study, following lesion, expression of Gpx1, Sod2, and Cat was significantly enhanced in mice overexpressing FXN compared to wild-type mice. Interestingly, Cat, which is a potent scavenger of H 2 O 2 and provides a powerful antioxidant defense in the retina, was found to be reduced after ischemia in wild-type animals, in agreement with previous studies in rats.…”

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

“…Scavenging of hydrogen peroxide by AO rescues frataxin deficiency in an ataxia model [87]. There are related investigations [88][89][90]. The ameliorating effect of L-carnitine pretreatment on oxidative DNA in ataxia was more prominent than for mannitol [91].…”