Genetically modified mesenchymal stem cells (MSCs) promote axonal regeneration and prevent hypersensitivity after spinal cord injury

AbstractSpinal cord injury (SCI) often leads to serious motor and sensory dysfunction of the limbs below the injured segment. SCI not only results in physical and psychological harm to patients but can also cause a huge economic burden on their families and society. As there is no effective treatment method, the prevention, treatment, and rehabilitation of patients with SCI have become urgent problems to be solved. In recent years, mesenchymal stem cells (MSCs) have attracted more attention in the treatment of SCI. Although MSC therapy can reduce injured volume and promote axonal regeneration, its application is limited by tumorigenicity, a low survival rate, and immune rejection. Accumulating literature shows that exosomes have great potential in the treatment of SCI. In this review, we summarize the existing MSC-derived exosome studies on SCI and discuss the advantages and challenges of treating SCI based on exosomes derived from MSCs.

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Bone marrow mesenchymal stem cells-derived exosomes reduce apoptosis and inflammatory response during spinal cord injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway

Human & Experimental Toxicology ◽

10.1177/09603271211003311 ◽

2021 ◽

pp. 096032712110033

Author(s):

Liying Fan ◽

Jun Dong ◽

Xijing He ◽

Chun Zhang ◽

Ting Zhang

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Motor Function ◽

Inflammatory Factors ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells ◽

Apoptosis And Inflammation

Spinal cord injury (SCI) is one of the most common destructive injuries, which may lead to permanent neurological dysfunction. Currently, transplantation of bone marrow mesenchymal stem cells (BMSCs) in experimental models of SCI shows promise as effective therapies. BMSCs secrete various factors that can regulate the microenvironment, which is called paracrine effect. Among these paracrine substances, exosomes are considered to be the most valuable therapeutic factors. Our study found that BMSCs-derived exosomes therapy attenuated cell apoptosis and inflammation response in the injured spinal cord tissues. In in vitro studies, BMSCs-derived exosomes significantly inhibited lipopolysaccharide (LPS)-induced PC12 cell apoptosis, reduced the secretion of pro-inflammatory factors including tumor necrosis factor (TNF)-α and IL (interleukin)-1β and promoted the secretion of anti-inflammatory factors including IL-10 and IL-4. Moreover, we found that LPS-induced protein expression of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear transcription factor-κB (NF-κB) was significantly downregulated after treatment with BMSCs-derived exosomes. In in vivo studies, we found that hindlimb motor function was significantly improved in SCI rats with systemic administration of BMSCs-derived exosomes. We also observed that the expression of pro-apoptotic proteins and pro-inflammatory factors was significantly decreased, while the expression of anti-apoptotic proteins and anti-inflammatory factors were upregulated in SCI rats after exosome treatment. In conclusion, BMSCs-derived exosomes can inhibit apoptosis and inflammation response induced by injury and promote motor function recovery by inhibiting the TLR4/MyD88/NF-κB signaling pathway, which suggests that BMSCs-derived exosomes are expected to become a new therapeutic strategy for SCI.

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CD157 in bone marrow mesenchymal stem cells mediates mitochondrial production and transfer to improve neuronal apoptosis and functional recovery after spinal cord injury

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02305-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Li ◽

Heyangzi Li ◽

Simin Cai ◽

Shi Bai ◽

Huabo Cai ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Motor Neurons ◽

Functional Recovery ◽

Mitochondrial Transfer ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells

Abstract Background Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. Methods We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. Results CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. Conclusion The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

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