Reduction of cystic cavity, promotion of axonal regeneration and sparing, and functional recovery with transplanted bone marrow stromal cell–derived Schwann cells after contusion injury to the adult rat spinal cord

2008 ◽  
Vol 9 (6) ◽  
pp. 600-610 ◽  
Author(s):  
Yukio Someya ◽  
Masao Koda ◽  
Mari Dezawa ◽  
Tomoko Kadota ◽  
Masayuki Hashimoto ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Schwann Cells ◽  
Functional Recovery ◽  
Axonal Regeneration ◽  
Immunohistochemical Analysis ◽  
Control Group ◽  
Cord Injury ◽  
Cystic Cavity

Object The authors previously reported that Schwann cells (SCs) could be derived from bone marrow stromal cells (BMSCs) in vitro and that they promoted axonal regeneration of completely transected rat spinal cords in vivo. The aim of the present study is to evaluate the efficacy of transplanted BMSC-derived SCs (BMSC-SCs) in a rat model of spinal cord contusion, which is relevant to clinical spinal cord injury. Methods Bone marrow stromal cells were cultured as plastic-adherent cells from the bone marrow of GFPtransgenic rats. The BMSC-SCs were derived from BMSCs in vitro with sequential treatment using beta-mercaptoethanol, all-trans-retinoic acid, forskolin, basic fibroblast growth factor, platelet derived–growth factor, and heregulin. Schwann cells were cultured from the sciatic nerve of neonatal, GFP-transgenic rats. Immunocytochemical analysis and the reverse transcriptase–polymerase chain reaction were performed to characterize the BMSC-SCs. For transplantation, contusions with the New York University impactor were delivered at T-9 in 10- to 11-week-old male Wistar rats. Four groups of rats received injections at the injury site 7 days postinjury: the first received BMSCSCs and matrigel, a second received peripheral SCs and matrigel, a third group received BMSCs and matrigel, and a fourth group received matrigel alone. Histological and immunohistochemical studies, electron microscopy, and functional assessments were performed to evaluate the therapeutic effects of BMSC-SC transplantation. Results Immunohistochemical analysis and reverse transcriptase–polymerase chain reaction revealed that BMSC-SCs have characteristics similar to SCs not only in their morphological characteristics but also in their immunocytochemical phenotype and genotype. Histological examination revealed that the area of the cystic cavity was significantly reduced in the BMSC-SC and SC groups compared with the control rats. Immunohistochemical analysis showed that transplanted BMSCs, BMSC-SCs, and SCs all maintained their original phenotypes. The BMSC-SC and SC groups had a larger number of tyrosine hydroxilase–positive fibers than the control group, and the BMSC-SC group had more serotonin-positive fibers than the BMSC or control group. The BMSC-SC group showed significantly better hindlimb functional recovery than in the BMSC and control group. Electron microscopy revealed that transplanted BMSC-SCs existed in association with the host axons. Conclusions Based on their findings, the authors concluded that BMSC-SC transplantation reduces the size of the cystic cavity, promotes axonal regeneration and sparing, results in hindlimb functional recovery, and can be a useful tool for spinal cord injury as a substitute for SCs.

Intraspinal cord graft of autologous activated Schwann cells efficiently promotes axonal regeneration and functional recovery after rat's spinal cord injury

2009 ◽  
Vol 1256 ◽  
pp. 149-161 ◽  
Author(s):  
De-Xiang Ban ◽  
Xiao-Hong Kong ◽  
Shi-Qing Feng ◽  
Guang-Zhi Ning ◽  
Jia-Tong Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Schwann Cells ◽  
Functional Recovery ◽  
Axonal Regeneration ◽  
Cord Injury

scholarly journals Transplantation of Neuregulin1-Overexpressing Bone Marrow Mesenchymal Cells Accelerates Motor Functional Recovery by Facilitating Neurite Outgrowth and Reducing Cell Apoptosis in Rat after Spinal Cord Injury

2020 ◽  
Author(s):  
Geng Wu ◽  
Herui Liu ◽  
Mei Zhu ◽  
Yang Wu ◽  
Yunlong Bai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Neurite Outgrowth ◽  
Pc12 Cells ◽  
Functional Recovery ◽  
Cell Apoptosis ◽  
Cord Injury ◽  
Neuronal Chromatolysis

Abstract Background: Bone marrow mesenchymal stem cells (BMSCs) transplantation offers an attractive strategy for treating multiply neurological diseases. Neuregulin1 (NRG1) plays fundamental roles in nervous system development and nerve repair. In this study, we aimed to investigate whether transplantation of NRG1-overexpressing BMSCs could alleviate spinal cord injury (SCI), and to explore the possible underling mechanisms. Methods: In vitro, NRG1-overexpressing BMSCs were constructed via plasmid transfection, and co-cultured with PC12 cells subjected to oxygen-glucose deprivation (OGD). Neurite outgrowth, cell viability and apoptosis of PC12 cells were evaluated. In vivo, BMSCs, empty-vector BMSCs and NRG1-overexpressing BMSCs were transplanted respectively into rats with SCI. Rat locomotor functions, neuronal chromatolysis, neurite outgrowth and cell apoptosis were assessed respectively. Results: The results showed that NRG1-overexpressing BMSCs in vitro significantly expedited neurite growth, elevated growth-associated protein 43 expression, enhanced cell viability and rescued ODG-induced apoptosis in PC12 cells. In vivo, transplantation of NRG1-overexpressing BMSCs notably accelerated rat motor functional recovery, attenuated neuronal chromatolysis, promoted neurite outgrowth and reduced cell apoptosis after SCI. Moreover, NRG1-overexpressing BMSCs were also able to regulate apoptosis-related proteins expression after SCI. Conclusions: These findings demonstrate that NRG1-overexpressing BMSCs can accelerate motor functional recovery by facilitating neurite outgrowth and reducing cell apoptosis after SCI, suggesting that NRG1-overexpressing BMSCs may be a promising candidate for the treatment of SCI.

scholarly journals Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 143
Author(s):  
Ganchimeg Davaa ◽  
Jin Young Hong ◽  
Tae Uk Kim ◽  
Seong Jae Lee ◽  
Seo Young Kim ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Cortex ◽  
Functional Recovery ◽  
Treadmill Exercise ◽  
Exercise Group ◽  
Control Group ◽  
Epigenetic Changes ◽  
Cord Injury ◽  
The Brain

Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.

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.

Transplantation of Neural Stem/Progenitor Cells at Different Locations in Mice with Spinal Cord Injury

2014 ◽  
Vol 23 (11) ◽  
pp. 1451-1464 ◽  
Author(s):  
Hiroki Iwai ◽  
Satoshi Nori ◽  
Soraya Nishimura ◽  
Akimasa Yasuda ◽  
Morito Takano ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Progenitor Cells ◽  
Functional Recovery ◽  
Control Group ◽  
Cord Injury ◽  
Neural Stem Progenitor Cells ◽  
Neurotropic Factor ◽  
Transplantation Site

Transplantation of neural stem/progenitor cells (NS/PCs) promotes functional recovery after spinal cord injury (SCI); however, few studies have examined the optimal site of NS/PC transplantation in the spinal cord. The purpose of this study was to determine the optimal transplantation site of NS/PCs for the treatment of SCI. Wild-type mice were generated with contusive SCI at the T10 level, and NS/PCs were derived from fetal transgenic mice. These NS/PCs ubiquitously expressed ffLuc-cp156 protein (Venus and luciferase fusion protein) and so could be detected by in vivo bioluminescence imaging 9 days postinjury. NS/PCs (low: 250,000 cells per mouse; high: 1 million cells per mouse) were grafted into the spinal cord at the lesion epicenter (E) or at rostral and caudal (RC) sites. Phosphate-buffered saline was injected into E as a control. Motor functional recovery was better in each of the transplantation groups (E-Low, E-High, RC-Low, and RC-High) than in the control group. The photon counts of the grafted NS/PCs were similar in each of the four transplantation groups, suggesting that the survival of NS/PCs was fairly uniform when more than a certain threshold number of cells were transplanted. Quantitative RT-PCR analyses demonstrated that brain-derived neurotropic factor expression was higher in the RC segment than in the E segment, and this may underlie why NS/PCs more readily differentiated into neurons than into astrocytes in the RC group. The location of the transplantation site did not affect the area of spared fibers, angiogenesis, or the expression of any other mediators. These findings indicated that the microenvironments of the E and RC sites are able to support NS/PCs transplanted during the subacute phase of SCI similarly. Optimally, a certain threshold number of NS/PCs should be grafted into the E segment to avoid damaging sites adjacent to the lesion during the injection procedure.

DHAM-BMSC Matrix Promotes Axonal Regeneration and Functional Recovery After Spinal Cord Injury in Adult Rats

2009 ◽  
pp. 110306202455053
Author(s):  
Hongsheng Liang ◽  
Peng Liang ◽  
Ye Xu ◽  
Jianing Wu ◽  
Tao Liang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Axonal Regeneration ◽  
Adult Rats ◽  
Cord Injury

scholarly journals Bone marrow stromal cell sheets may promote axonal regeneration and functional recovery with suppression of glial scar formation after spinal cord transection injury in rats

2017 ◽  
Vol 26 (3) ◽  
pp. 388-395 ◽  
Author(s):  
Akinori Okuda ◽  
Noriko Horii-Hayashi ◽  
Takayo Sasagawa ◽  
Takamasa Shimizu ◽  
Hideki Shigematsu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Bone Marrow ◽  
Ascorbic Acid ◽  
Functional Recovery ◽  
Axonal Regeneration ◽  
Glial Scar ◽  
Scar Formation ◽  
Gelatin Sponge ◽  
Cell Sheets ◽  
Locomotor Function

OBJECTIVE Transplantation of bone marrow stromal cells (BMSCs) is a theoretical potential as a therapeutic strategy in the treatment of spinal cord injury (SCI). Although a scaffold is sometimes used for retaining transplanted cells in damaged tissue, it is also known to induce redundant immunoreactions during the degradation processes. In this study, the authors prepared cell sheets made of BMSCs, which are transplantable without a scaffold, and investigated their effects on axonal regeneration, glial scar formation, and functional recovery in a completely transected SCI model in rats. METHODS BMSC sheets were prepared from the bone marrow of female Fischer 344 rats using ascorbic acid and were cryopreserved until the day of transplantation. A gelatin sponge (GS), as a control, or BMSC sheet was transplanted into a 2-mm-sized defect of the spinal cord at the T-8 level. Axonal regeneration and glial scar formation were assessed 2 and 8 weeks after transplantation by immunohistochemical analyses using anti-Tuj1 and glial fibrillary acidic protein (GFAP) antibodies, respectively. Locomotor function was evaluated using the Basso, Beattie, and Bresnahan scale. RESULTS The BMSC sheets promoted axonal regeneration at 2 weeks after transplantation, but there was no significant difference in the number of Tuj1-positive axons between the sheet- and GS-transplanted groups. At 8 weeks after transplantation, Tuj1-positive axons elongated across the sheet, and their numbers were significantly greater in the sheet group than in the GS group. The areas of GFAP-positive glial scars in the sheet group were significantly reduced compared with those of the GS group at both time points. Finally, hindlimb locomotor function was ameliorated in the sheet group at 4 and 8 weeks after transplantation. CONCLUSIONS The results of the present study indicate that an ascorbic acid–induced BMSC sheet is effective in the treatment of SCI and enables autologous transplantation without requiring a scaffold.

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