Contributions
Abstract: P669
Type: Poster
Abstract Category: Therapy - disease modifying - Neuroprotection
Cell-based therapy with mesenchymal stromal cells (MSCs) is being investigated as a treatment for multiple sclerosis (MS) in view of neuroprotective and anti-inflammatory properties of MSCs. However, we have recently shown that MSCs isolated from patients with MS (MS MSCs) have reduced expansion potential ex vivo and fail to protect neurons in a model of oxidative stress. Given that many MSC reparative properties are mediated via the MSC secretome - the collective term for factors secreted as soluble molecules and/or in extracellular vesicles - we compared the composition of media conditioned by MSCs isolated from patients with MS (MS MSCcm) and control subjects (MSCcm).
MSCs were isolated from marrow donated by those undergoing total hip replacement or participating in the "ACTiMuS" trial of unselected autologous marrow infusion in progressive MS (NCT01815632). Using tandem mass spectrometry, we noted relative reductions in the concentration of factors predisposing to increased oxidative stress in age-matched MS MSCcm including Cu-Zn superoxide dismutase1 (SOD1), mitochondrial fumarase, peroxiredoxin1 and glutathione transferase1. Reduced concentration of SOD1 was quantified using ELISA and reduced expression of SOD1, fumarase and glutathione transferase1 confirmed using western blot analysis. We also observed reductions in the expression of master regulators of ROS scavenging enzymes in MS MSCs including peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC1-α) and nuclear factor erythroid 2-related factor 2 (Nrf2). Interestingly, there was no significant change in expression of the peroxisomal enzyme catalase or in MSC secretion of a wide range of known neuroprotective growth factors.
Our findings suggest that MS MSCs have altered secretion and expression of a number of proteins relevant to antioxidant defence and point towards altered mitochondrial function. We note that others have demonstrated that replicative senescence in MSCs is associated with reduced expression of antioxidant enzymes, raising the possibility of a link between oxidative stress and our finding of reduced MS MSC expansion potential. Further work will explore mitochondrial function and transfer in MS MSCs in greater detail and will determine whether the observed changes contribute to increased susceptibility of MS MSCs to oxidative stress as well as underlying the observed impairments in MSC-mediated neuroprotection and expansion.
Disclosure: The authors have no relevant disclosures.
Abstract: P669
Type: Poster
Abstract Category: Therapy - disease modifying - Neuroprotection
Cell-based therapy with mesenchymal stromal cells (MSCs) is being investigated as a treatment for multiple sclerosis (MS) in view of neuroprotective and anti-inflammatory properties of MSCs. However, we have recently shown that MSCs isolated from patients with MS (MS MSCs) have reduced expansion potential ex vivo and fail to protect neurons in a model of oxidative stress. Given that many MSC reparative properties are mediated via the MSC secretome - the collective term for factors secreted as soluble molecules and/or in extracellular vesicles - we compared the composition of media conditioned by MSCs isolated from patients with MS (MS MSCcm) and control subjects (MSCcm).
MSCs were isolated from marrow donated by those undergoing total hip replacement or participating in the "ACTiMuS" trial of unselected autologous marrow infusion in progressive MS (NCT01815632). Using tandem mass spectrometry, we noted relative reductions in the concentration of factors predisposing to increased oxidative stress in age-matched MS MSCcm including Cu-Zn superoxide dismutase1 (SOD1), mitochondrial fumarase, peroxiredoxin1 and glutathione transferase1. Reduced concentration of SOD1 was quantified using ELISA and reduced expression of SOD1, fumarase and glutathione transferase1 confirmed using western blot analysis. We also observed reductions in the expression of master regulators of ROS scavenging enzymes in MS MSCs including peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC1-α) and nuclear factor erythroid 2-related factor 2 (Nrf2). Interestingly, there was no significant change in expression of the peroxisomal enzyme catalase or in MSC secretion of a wide range of known neuroprotective growth factors.
Our findings suggest that MS MSCs have altered secretion and expression of a number of proteins relevant to antioxidant defence and point towards altered mitochondrial function. We note that others have demonstrated that replicative senescence in MSCs is associated with reduced expression of antioxidant enzymes, raising the possibility of a link between oxidative stress and our finding of reduced MS MSC expansion potential. Further work will explore mitochondrial function and transfer in MS MSCs in greater detail and will determine whether the observed changes contribute to increased susceptibility of MS MSCs to oxidative stress as well as underlying the observed impairments in MSC-mediated neuroprotection and expansion.
Disclosure: The authors have no relevant disclosures.