Myelin Debris Stimulates NG2/CSPG4 Expression in Bone Marrow-Derived Macrophages in the Injured Spinal Cord

Although the increased expression of members of the chondroitin sulfate proteoglycan family, such as neuron-glial antigen 2 (NG2), have been well documented after an injury to the spinal cord, a complete picture as to the cellular origins and function of this NG2 expression has yet to be made. Using a spinal cord injury (SCI) mouse model, we describe that some infiltrated bone marrow-derived macrophages (BMDMΦ) are early contributors to NG2/CSPG4 expression and secretion after SCI. We demonstrate for the first time that a lesion-related form of cellular debris generated from damaged myelin sheaths can increase NG2/CSPG4 expression in BMDMΦ, which then exhibit enhanced proliferation and decreased phagocytic capacity. These results suggest that BMDMΦ may play a much more nuanced role in secondary spinal cord injury than previously thought, including acting as early contributors to the NG2 component of the glial scar.

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Preserved granulocyte formation and function, as well as bone marrow innervation, in subjects with complete spinal cord injury

British Journal of Haematology ◽

10.1111/j.1365-2141.2004.05085.x ◽

2004 ◽

Vol 126 (6) ◽

pp. 870-877 ◽

Cited By ~ 8

Author(s):

Per Ole Iversen ◽

Anne Nicolaysen ◽

Nils Hjeltnes ◽

Arild Njå ◽

Haakon B. Benestad

Keyword(s):

Spinal Cord ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Cord Injury ◽

Complete Spinal Cord Injury ◽

And Function

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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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Editor’s Note: Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02197-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Virginie Neirinckx ◽

Gulistan Agirman ◽

Cécile Coste ◽

Alice Marquet ◽

Valérie Dion ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mouse Model ◽

Neural Crest ◽

Neural Crest Stem Cells ◽

Adult Bone Marrow ◽

Cord Injury ◽

Adult Bone

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Pretreatment with kaempferol attenuates microglia-mediate neuroinflammation by inhibiting MAPKs–NF–κB signaling pathway and pyroptosis after secondary spinal cord injury

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2021.03.037 ◽

2021 ◽

Vol 168 ◽

pp. 142-154

Author(s):

Zhongyuan Liu ◽

Xinqiang Yao ◽

Baihui Sun ◽

Wangsheng Jiang ◽

Congrui Liao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signaling Pathway ◽

Cord Injury ◽

Secondary Spinal Cord Injury

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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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Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages

Inflammation ◽

10.1007/s10753-021-01507-x ◽

2021 ◽

Author(s):

Shangrila Parvin ◽

Clintoria R. Williams ◽

Simone A. Jarrett ◽

Sandra M. Garraway

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Inflammatory Cytokine ◽

Cardiovascular Health ◽

Mrna Levels ◽

Post Injury ◽

Cord Injury ◽

And Function ◽

The Impact

Abstract— Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.

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