Abstract
Cell-therapy modalities using mesenchymal stem (MSCs) in experimental strokes are being investigated due to the role of MSCs in neuroprotection and regeneration. It is necessary to know the sequence of events that occur during stress and how MSCs complement the rescue of neuronal cell death mediated by [Ca2+]i and reactive oxygen species (ROS). In the current study, SH-SY5Y-differentiated neuronal cells were subjected to in vitro cerebral ischemia-like stress and were experimentally rescued from cell death using an MSCs/neuronal cell coculture model. Neuronal cell death was characterized by the induction of proinflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and -12, up to 35-fold with corresponding downregulation of anti-inflammatory cytokine transforming growth factor (TGF)-β, IL-6 and -10 by approximately 1 to 7 fold. Increased intracellular calcium [Ca2+]i and ROS clearly reaffirmed oxidative stress-mediated apoptosis, while upregulation of nuclear factor NF-κB and cyclo-oxygenase (COX)-2 expressions, along with ~41% accumulation of early and late phase apoptotic cells, confirmed ischemic stress-mediated cell death. Stressed neuronal cells were rescued from death when cocultured with MSCs via increased expression of anti-inflammatory cytokines (TGF-β, 17%; IL-6, 4%; and IL-10, 13%), significantly downregulated NF-κB and proinflammatory COX-2 expression. Further accumulation of early and late apoptotic cells was diminished to 23%, while corresponding cell death decreased from 40% to 17%. Low superoxide dismutase 1 (SOD1) expression at the mRNA level was rescued by MSCs coculture, while no significant changes were observed with catalase (CAT) and glutathione peroxidase (GPx). Interestingly, increased serotonin release into the culture supernatant was proportionate to the elevated [Ca2+]i and corresponding ROS, which were later rescued by the MSCs coculture to near normalcy. Taken together, all of these results primarily support MSCs-mediated modulation of stressed neuronal cell survival in vitro.
Highlights
Neuronal cell damage during cerebral ischemia or stroke is a serious neurological complication that limits survival and/or functional recovery [1]
In the current study, we investigated neuronal cell death mediated by elevated [Ca2+ ]i levels and oxidative stressors such as reactive oxygen species (ROS) and proinflammatory cytokines that are modulated by mesenchymal stem (MSCs) cocultures in vitro
It was evident that MSCs cocultured with stressed neuronal cells can alleviate the harmful effect of ischemia-mediated oxidative stress and apoptosis
Summary
Neuronal cell damage during cerebral ischemia or stroke is a serious neurological complication that limits survival and/or functional recovery [1]. High concentrations of unsaturated fatty acids and low concentrations of oxidant scavengers are other factors that are favorable to catalyze free-radical formations and immature cells contributing to overall stress pathology [2]. The cascade of accumulation or depletion of stress factors is questionable, while, in cerebral ischemia or stroke, one or more of these factors either directly or indirectly predispose neuronal cells to death [3]. Many detailed studies in the recent past have characterized neuronal cell death well, and therapeutic interventions have had little or no impact on cellular recovery [5]. Neuronal damage is a characteristic pathology associated with many noninflammatory-associated neurodegenerative diseases
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
