Abstract
The potential of autologous cell‐based therapies including those using multipotent mesenchymal stromal cells (MSCs) is being investigated for multiple sclerosis (MS) and other neurological conditions. However, the phenotype of MSC in neurological diseases has not been fully characterized. We have previously shown that MSC isolated from patients with progressive MS (MS‐MSC) have reduced expansion potential, premature senescence, and reduced neuroprotective potential in vitro. In view of the role of antioxidants in ageing and neuroprotection, we examined the antioxidant capacity of MS‐MSC demonstrating that MS‐MSC secretion of antioxidants superoxide dismutase 1 (SOD1) and glutathione S‐transferase P (GSTP) is reduced and correlates negatively with the duration of progressive phase of MS. We confirmed reduced expression of SOD1 and GSTP by MS‐MSC along with reduced activity of SOD and GST and, to examine the antioxidant capacity of MS‐MSC under conditions of nitrosative stress, we established an in vitro cell survival assay using nitric oxide‐induced cell death. MS‐MSC displayed differential susceptibility to nitrosative stress with accelerated senescence and greater decline in expression of SOD1 and GSTP in keeping with reduced expression of master regulators of antioxidant responses nuclear factor erythroid 2‐related factor 2 and peroxisome proliferator‐activated receptor gamma coactivator 1‐α. Our results are compatible with dysregulation of antioxidant responses in MS‐MSC and have significant implications for development of autologous MSC‐based therapies for MS, optimization of which may require that these functional deficits are reversed. Furthermore, improved understanding of the underlying mechanisms may yield novel insights into MS pathophysiology and biomarker identification. Stem Cells Translational Medicine 2018;7:748–758
Highlights
Reactive oxygen and nitrogen species (ROS/RNS) are by-products of normal aerobic metabolism and are involved in the complex regulation of several signaling pathways including cell proliferation, survival, and inflammation [1,2,3,4,5,6,7,8,9]
Using LC-MSMS, superoxide dismutase 1 (SOD1), and Glutathione S-Transferase Pi 1 (GSTP1) were detected in the secretome of C-mesenchymal stromal cells (MSCs) and multiple sclerosis (MS)-MSC but there was a relative reduction in the secretion of both antioxidants by MS-MSC (Fig. 1A, 1D)
The results were confirmed using enzyme-linked immunosorbent assay (ELISA); an independent negative effect of the presence of progressive MS was seen on secretion of both SOD1 and GSTP1 when the effect of age was taken into consideration (Fig. 1B, 1E)
Summary
Reactive oxygen and nitrogen species (ROS/RNS) are by-products of normal aerobic metabolism and are involved in the complex regulation of several signaling pathways including cell proliferation, survival, and inflammation [1,2,3,4,5,6,7,8,9]. Nitrosative stress that contributes to pathology in a range of clinical contexts including ageing and multiple sclerosis (MS) [10,11,12,13]. Mesenchymal stromal cells (MSCs) have a range of properties of relevance to cell therapy for MS including anti-inflammatory, immunomodulatory, and antioxidant paracrine activity [14]. Given the wealth of preclinical data demonstrating amelioration of disease and their favorable safety profile, there has been rapid clinical translation of autologous MSC-based cell therapy for MS [15]. Studies have shown that MSC function changes with age and chronic exposure to a proinflammatory environment [9,16] and few data are available regarding MSC function in MS
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