Objective The therapeutic benefits of exosomes obtained from mesenchymal stem cells (MSCs) in acute spinal cord injury (SCI) have been demonstrated in recent years, but the precise mechanisms remain unknown. In this study, the efficacy and mechanisms of MSC-derived exosomes (MSC-Exo) in acute SCI were investigated.
Methods By utilizing a BV2 ferroptosis cellular model and an SCI rat model, we investigated the effects of MSC-Exo on iron death related indicators and NF-E2 related factor 2 (Nrf2)/GTP cyclolase I (GCH1)/5,6,7,8-tetrahydrobiopterin (BH4) signaling axis, as well as their therapeutic effects on SCI rats.
Results The results revealed that MSC-Exo effectively inhibited the production of ferrous iron, lipid peroxidation products malonaldehyde and reactive oxygen species, and ferroptosis-promoting factor prostaglandin-endoperoxide synthase 2. Concurrently, they upregulated ferroptosis suppressors FTH-1 (ferritin heavy chain 1), SLC7A11 (solute carrier family 7 member 11), FSP1 (ferroptosis suppressor protein 1), and GPX4 (glutathione peroxidase 4), contributing to enhanced neurological recovery in SCI rats. Further analysis showed the Nrf2/GTP/BH4 signaling pathway’s critical role in suppressing ferroptosis. Additionally, MSC-Exo was found to inhibit lipopolysaccharide-induced ferroptosis in BV2 cells and SCI rats by activating the Nrf2/GCH1/BH4 axis.
Conclusion In summary, the study demonstrates that MSC-Exo mitigates microglial cell ferroptosis via the Nrf2/GCH1/BH4 axis, showing potential for preserving and restoring neurological function post-SCI.
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Objective Herein, we investigated whether mesenchymal stem cells (MSCs) transplantation combined with electroacupuncture (EA) treatment could decrease the proportion of proinflammatory microglia/macrophages and neurotoxic A1 reactive astrocytes and inhibit glial scar formation to enhance axonal regeneration after spinal cord injury (SCI).
Methods Adult rats were divided into 5 groups after complete transection of the spinal cord at the T10 level: a control group, a nonacupoint EA (NA-EA) group, an EA group, an MSC group, and an MSCs+EA group. Immunofluorescence labeling, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blots were performed.
Results The results showed that MSCs+EA treatment reduced the proportion of proinflammatory M1 subtype microglia/macrophages, but increased the differentiation of anti-inflammatory M2 phenotype cells, thereby suppressing the mRNA and protein expression of proinflammatory cytokines (tumor necrosis factor-α and IL-1β) and increasing the expression of an anti-inflammatory cytokine (interleukin [IL]-10) on days 7 and 14 after SCI. The changes in expression correlated with the attenuated neurotoxic A1 reactive astrocytes and glial scar, which in turn facilitated the axonal regeneration of the injured spinal cord. In vitro, the proinflammatory cytokines increased the level of proliferation of astrocytes and increased the expression levels of C3, glial fibrillary acidic protein, and chondroitin sulfate proteoglycan. These effects were blocked by administering inhibitors of ErbB1 and signal transducer and activator of transcription 3 (STAT3) (AG1478 and AG490) and IL-10.
Conclusion These findings showed that MSCs+EA treatment synergistically regulated the microglia/macrophage subpopulation to reduce inflammation, the formation of neurotoxic A1 astrocytes, and glial scars. This was achieved by downregulating the ErbB1-STAT3 signal pathway, thereby providing a favorable microenvironment conducive to axonal regeneration after SCI.
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Objective Tyrosine hydroxylase (TH) is a rate-limiting enzyme in dopamine synthesis, making the enhancement of its activity a target for ensuring sufficient dopamine levels. Rat bone marrow mesenchymal stem cells (rBM-MSCs) are known to synthesize TH after differentiating into neuronal cells through chemical induction, but the effect of its ectopic expression on these cells has not yet been determined. This study investigated the effects of ectopic recombinant TH expression on the stemness characteristics of rBM-MSCs.
Methods After cloning, a cell line with stable TH expression was maintained, and the proliferation, the gene expression profile, and differentiation potential of rBM-MSCs were analyzed. Analysis of the cells showed an increment in the proliferation rate that could be reversed by the neutralization of TH.
Results The constitutive expression of TH in rBM-MSCs was successfully implemented, without significantly affecting their osteogenic and adipogenic differentiation potential. TH expression improved the expression of other neuronal markers, such as glial fibrillary acidic protein, β-tubulin, nestin, and c-Fos, confirming the neurogenic differentiation capacity of the stem cells. The expression of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) significantly increased after the chemical induction of neurogenic differentiation.
Conclusion In this study, the expression of recombinant TH improved the neuroprotective effect of MSCs by upregulating the expression of BDNF and CNTF. Although the neuronal markers were upregulated, the expression of recombinant TH alone in rBM-MSCs was not sufficient for MSCs to differentiate into neurogenic cell lines.
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Therapeutic potentials of human microfluidic encapsulated conjunctival mesenchymal stem cells on the rat model of Parkinson's disease Meysam Forouzandeh, Mohammad Reza Bigdeli, Hossein Mostafavi, Samad Nadri, Mehdi Eskandari Experimental and Molecular Pathology.2021; 123: 104703. CrossRef
Effects of GDNF-Transfected Marrow Stromal Cells on Rats with Intracerebral Hemorrhage Li Deng, Xiaoqing Gao, Guangbi Fan, Chaoxian Yang Journal of Stroke and Cerebrovascular Diseases.2019; 28(9): 2555. CrossRef
THE EFFECT OF DRAG FORCE AND FLOW RATE ON MESENCHYMAL STEM CELLS IN PACKED-BED PERFUSION BIOREACTOR Gökhan DURUKSU Eskişehir Teknik Üniversitesi Bilim ve Teknoloji Dergisi - C Yaşam Bilimleri Ve Biyoteknoloji.2019; 8(2): 179. CrossRef
OBJECTIVE Mesenchymal stem cells (MSCs) have shown promise in potentially repairing injured spinal cord. These and similar cell types are being tested clinically, but the understanding about delivering method and subsequent results is lacking. This study was designed to compare the MSCs engraftment results after intralesional, intracisternal, or intravenous injection in a rat with spinal cord injury (SCI). METHODS A total of 48 male Sprague-Dawley rats (300-350 g in size) were used with 12 in each group. Allogenic MSCs were cultured from human bone marrow aspirates. The SCI was induced using an NYU (New York University) impactor and MSCs were transplanted 1 week after the SCI. Behavioral testing was performed weekly for 6 weeks. The recipients were analyzed histologically to evaluate the extent of cell delivery and survival at the injury site. RESULTS All three experimental groups showed better behavioral recovery compared with the control group since 6 weeks after stem cell injection (p<0.05). The intracisternal injection group showed the best functional improvement (p<0.05). The intralesional injection group showed the best engraftment until 4 weeks after stem cell injection (p<0.05). A number of the injected MSCs were trapped in the spleen in the intravenous injection group. CONCLUSION Transplantation of stem cells by a variety of routes can deliver cells with the potential to repair injured spinal cord. Intracisternal injection can easily be translated to patients after some modifications, thus accelerating clinical application of cell therapies.
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