Delayed accumulation of activated macrophages and inhibition of remyelination after spinal cord injury in an adult rodent model

2008 ◽  
Vol 8 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Masaaki Imai ◽  
Masahiko Watanabe ◽  
Kaori Suyama ◽  
Takahiro Osada ◽  
Daisuke Sakai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Green Fluorescent Protein ◽  
Fluorescent Protein ◽  
Activated Macrophages ◽  
Cord Injury ◽  
Myelin Debris ◽  
Chemotactic Factors ◽  
Green Fluorescent

Object Inhibition of remyelination is part of the complex problem of persistent dysfunction after spinal cord injury (SCI), and residual myelin debris may be a factor that inhibits remyelination. Phagocytosis by microglial cells and by macrophages that migrate from blood vessels plays a major role in the clearance of myelin debris. The object of this study was to investigate the mechanisms underlying the failure of significant remyelination after SCI. Methods The authors investigated macrophage recruitment and related factors in rats by comparing a contusion model (representing contusive SCI with residual myelin debris and failure of remyelination) with a model consisting of chemical demyelination by lysophosphatidylcholine (representing multiple sclerosis with early clearance of myelin debris and remyelination). The origin of infiltrating macrophages was investigated using mice transplanted with bone marrow cells from green fluorescent protein–transfected mice. The changes in levels of residual myelin debris and the infiltration of activated macrophages in demyelinated lesions were investigated by immunostaining at 2, 4, and 7 days postinjury. To investigate various factors that might be involved, the authors also investigated gene expression of macrophage chemotactic factors and adhesion factors. Results Activated macrophages coexpressing green fluorescent protein constituted the major cell population in the lesions, indicating that the macrophages in both models were mainly derived from the bone marrow, and that very few were derived from the intrinsic microglia. Immunostaining showed that in the contusion model, myelin debris persisted for a long period, and the infiltration of macrophages was significantly delayed. Among the chemotactic factors, the levels of monocyte chemoattractant protein–1 and granulocyte–macrophage colony-stimulating factor were lower in the contusion model at 2 and 4 days postinjury. Conclusions The results suggest that the delayed infiltration of activated macrophages is related to persistence of myelin debris after contusive SCI, resulting in the inhibition of remyelination.

scholarly journals Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Accelerate Functional Recovery After Spinal Cord Injury by Promoting the Phagocytosis of Macrophages to Clean Myelin Debris

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaolong Sheng ◽  
Jinyun Zhao ◽  
Miao Li ◽  
Yan Xu ◽  
Yi Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Immune Therapy ◽  
Phagocytic Ability ◽  
Therapy Strategy ◽  
Macrophage Phagocytosis ◽  
Cord Injury ◽  
Myelin Debris

Macrophage phagocytosis contributes predominantly to processing central nervous system (CNS) debris and further facilitates neurological function restoration after CNS injury. The aims of this study were to evaluate the effect of bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BMSC-Exos) on the phagocytic capability of macrophages to clear myelin debris and to investigate the underlying molecular mechanism during the spinal cord injury (SCI) process. This work reveals that monocyte-derived macrophages (MDMs) infiltrating into the SCI site could efficiently engulf myelin debris and process phagocytic material. However, the phagocytic ability of macrophages to clear tissue debris is compromised after SCI. The administration of BMSC-Exos as an approach for SCI treatment could rescue macrophage normal function by improving the phagocytic capability of myelin debris internalization, which is beneficial for SCI repair, as evidenced by better axon regrowth and increased hindlimb locomotor functional recovery in a rodent model. Examination of macrophage treatment with BMSC-Exos revealed that BMSC-Exos could promote the capacity of macrophages to phagocytose myelin debris in vitro and could create a regenerative microenvironment for axon regrowth. In addition, we confirmed that BMSC-Exo treatment resulted in improved phagocytosis of engulfed myelin debris by promoting the expression of macrophage receptor with collagenous structure (MARCO) in macrophages. The inhibition of MARCO with PolyG (a MARCO antagonist) impaired the effect of BMSC-Exos on the phagocytic capacity of macrophages and resulted in compromised myelin clearance at the lesion site, leading to further tissue damage and impaired functional healing after SCI. In conclusion, these data indicated that targeting the phagocytic ability of macrophages may have therapeutic potential for the improvement in functional healing after SCI. The administration of BMSC-Exos as a cell-free immune therapy strategy has wide application prospects for SCI treatment.

scholarly journals Intravenous Administration of Heat Shock-Treated MSCs Can Improve Neuroprotection and Neuroregeneration in Canine Spinal Cord Injury Model

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 2164
Author(s):  
Woo Keyoung Kim ◽  
Wan Hee Kim ◽  
Oh-Kyeong Kweon ◽  
Byung-Jae Kang
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Heat Shock ◽  
Cellular Therapy ◽  
Fluorescent Protein ◽  
Cell Damage ◽  
Spinal Cord Injury Model ◽  
Cord Injury ◽  
Lactated Ringer's Solution ◽  
Green Fluorescent

Transplantation of mesenchymal stem cells (MSCs) is a promising treatment for spinal cord injury (SCI). However, many transplanted cells die within a few days, eventually limiting the efficacy of cellular therapy. To overcome this problem, we focused on the potential of heat shock (HS) proteins in facilitating recovery from cell damage and protecting against cytotoxicity. PCR results showed that the expression of neurotrophic factor, anti-inflammatory, stemness, and homing genes increased in HS-treated MSCs. We investigated whether HS-treated MSCs could promote recovery of hindlimb function in an acute canine SCI model. We compared the effects of intravenous transplantation with (i) lactated Ringer’s solution as a control, (ii) green fluorescent protein-expressing MSCs (MSCs-GFP), and (iii) GFP-expressing and HS-treated MSCs (MSCs-GFP-HS). Spinal cords were harvested at four weeks and used for Western blot and histopathological analyses. The MSCs-GFP-HS group showed significant improvements in hindlimb function from weeks 3 and 4 compared with the other groups. This group also showed higher expression of neural markers, fewer intervening fibrotic changes, and pronounced myelination. These results suggest that induction of an HS response in MSCs could promote neural sparing. In conclusion, transplantation of HS-treated MSCs could improve neuroprotection and neuroregeneration in acute SCI.

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

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.

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

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.

Safety of Autologous Bone Marrow Stromal Cell Transplantation in Dogs with Acute Spinal Cord Injury

2012 ◽  
Vol 41 (4) ◽  
pp. 437-442 ◽  
Author(s):  
Hidetaka Nishida ◽  
Masanari Nakayama ◽  
Hiroshi Tanaka ◽  
Masahiko Kitamura ◽  
Shingo Hatoya ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Cell Transplantation ◽  
Stromal Cell ◽  
Bone Marrow Stromal Cell ◽  
Autologous Bone Marrow ◽  
Marrow Stromal Cell ◽  
Cord Injury ◽  
Autologous Bone

scholarly journals Efficacy of autologous bone marrow mononuclear cell transplantation in dogs with chronic spinal cord injury

2020 ◽  
Vol 10 (2) ◽  
pp. 206-215
Author(s):  
Katsutoshi Tamura ◽  
Noritaka Maeta
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Cell Transplantation ◽  
Mononuclear Cell ◽  
Motor Neurons ◽  
Research Work ◽  
Autologous Bone Marrow ◽  
Bone Marrow Mononuclear Cell ◽  
Cord Injury

Background: Spinal cord injury (SCI) is relatively common in dogs and is a devastating condition involving loss of sensory neurons and motor  neurons. However, the main clinical protocol for the management of SCI is surgery to decompress and stabilize the vertebra. Cell transplantation therapy is a very promising strategy for the treatment of chronic SCI, but extensive preclinical and clinical research work remains.Aim: The aim of this study is to confirm the effect of bone marrow-derived mononuclear cell (BM-MNC) transplantation for chronic SCI in dogs.Methods: We tested the treatment efficiency of chronic SCI in 12 dogs using BM-MNC transplantation. Neurological evaluation used the Texas Spinal Cord Injury Scale (TSCIS). Concurrently, we characterized the transplanted cells by evaluation using quantitative real-time polymerase chain reaction, flow cytometry, and enzyme-linked immunosorbent assay.Result: All dogs had a pre-transplantation TSCIS score of 0. Two animals did not show any improvement in their final TSCIS scores. The remaining 10 dogs (83.4%) achieved improvement in the final TSCIS scores. Five of them (41.7%) regained ambulatory function with a TSCIS score greater than 10. We determined that canine BM-MNCs expressed hepatocyte growth factor (HGF) mRNA at higher levels than other cytokines, with significant  increases in HGF levels in cerebrospinal fluid within 48 hours after autologous BM-MNC transplantation into the subarachnoid space of the spinal dura matter in dogs.Conclusions: BM-MNC transplantation may be effective for at least some cases of chronic SCI. Keywords: Bone marrow-derived mononuclear cell, Cell therapy, Spinal cord injury.

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