CELL THERAPY APPROACH FOR TREATING OXIDATIVE DAMAGE IN MULTIPLE SCLEROSIS?

In the last few years, clinical trials of stem cell therapies have begun for neurological disorders. A number of trial studies, particularly in multiple sclerosis the potential of bone marrow-derived stem cell therapies, have been published. The first few experiments were regarding stem cells’ potential and their capability to differentiate into central nervous system cells and replace lost or damaged cells in diseased tissue.

Indeed, many other researchers are studying myelin repair. However, a potentially more clinically applicable function of stem cells is their ability to modulate disease processes. Mesenchymal stem cells have potent immune-modulatory effects in experimental models. These cells can also secrete various substances that may weaken disease processes or provide trophic support for the diseased nervous system. In MS, oxidative stress is mainly associated with severe damage to the axons and myelin, leading to multiple clinical symptoms. For many years, developing therapies have been ongoing which can reduce the damage done through oxidation stress and thus reduce injuries to tissues.

Mechanisms of Tissue Damage in MS

Multiple sclerosis has characteristically been considered a T-cell-dependent process associated with macrophage-mediated demyelination driven by myelin-specific autoantigens. Evidence for the central role of T cells includes the presence of Th1 (T helper) cytokines, receptors, and cells in the CSF, circulation, and lesions of MS patients. However, in recent years, it has become clear that the immunological interplay in MS is much more complicated than first thought.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated as part of normal cellular physiology. However, if there is overproduction of ROS or a failure of antioxidant mechanisms, these species can cause damage to lipids, proteins, and nucleic acids and may lead to cell death. CNS neurons are constantly exposed to low levels of these oxidative/nitrative species, which can easily be dealt with by inherent repair and protection mechanisms.

High levels of NO, peroxynitrite, and superoxide have all been demonstrated in spinal fluid from patients with MS. Reactive nitrogen species have a wide variety of effects on cells through the modification of protein structure and function: they inhibit several enzymes involved in respiration, thereby disrupting mitochondrial function and reducing ATP content as demonstrated in neurons exposed to NO. NO is known to affect several of the enzymes involved in oxidative defense, including catalase.

There are several reasons why the CNS is particularly vulnerable to oxidative damage. These include the fact that brain tissue is very active in oxidative metabolism leading to relatively high levels of intracellular superoxide: the limited ability of the CNS to engage in anaerobic respiration resulting in high levels of superoxide in a hypoxic environment. Cellular features predisposing to oxidative damage within the oligodendrocyte population, including low levels of antioxidant defenses, membrane elaborations, and high iron content; the composition of myelin as a preferential target of ROS due to high protein.

Cell-Based Approach to Oxidative Damage

Several different cell-based approaches to repair and protect against tissue damage in MS have been postulated and subject to intense research. Examples include hematopoietic stem cells used in an immune-reprogramming capacity and neural stem cells predominantly being explored for their regenerative potential.

Meanwhile, mesenchymal stem cells (MSCs) have emerged as promising candidates in protecting neurones against the oxidative damage encountered in MS. The potential therapeutic applications of MSCs for neurological disorders have generated great interest. In vitro studies have shown that MSC-conditioned media can confer a neuroprotective effect against oxidative insult to both primary cortical and cerebellar neurons and also neuroblastoma cell lines.

Evidence suggests that one method by which MSCs exert a neuroprotective effect against oxidative stress is through the modulation of signaling pathways involved in antioxidant and stress-related processes. Another mechanism by which MSCs can exert a direct antioxidant effect is through the secretion of antioxidant molecules. We have recently shown that bone-marrow-derived MSCs secrete the extracellular antioxidant molecule superoxide dismutase 3.

References

Witherick, J., Wilkins, A., Scolding, N. and Kemp, K., 2010. Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment. Autoimmune diseases, 2011.

Lee, D.H., Gold, R. and Linker, R.A., 2012. Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. International journal of molecular sciences, 13(9), pp.11783-11803.

Ruiz-Argüelles, G.J. and Gómez-Almaguer, D., 2017. Hematopoietic stem cell transplants for persons with multiple sclerosis: Is this the best therapeutic option. Medicina Universitaria, 19(77), pp.208-209.