Collagen/heparin sulfate scaffold combined with mesenchymal stem cells treatment for canines with spinal cord injury: A pilot feasibility study

Background: Due to endogenous neuronal deficiency and glial scar formation, spinal cord injury (SCI) often leads to irreversible neurological loss. Accumulating evidence has shown that a suitable scaffold has important value for promoting nerve regeneration after SCI. Collagen/heparin sulfate scaffold (CHSS) has shown effect for guiding axonal regeneration and decreasing glial scar deposition after SCI. The current research aimed to evaluate the utility of the CHSSs adsorbed with mesenchymal stem cells (MSCs) on nerve regeneration, and functional recovery after acute complete SCI. Methods: CHSSs were prepared, and evaluated for biocompatibility. The CHSSs adsorbed with MSCs were transplanted into these canines with complete SCI. Results: We observed that MSCs had good biocompatibility with CHSSs. In complete transverse SCI models, the implantation of CHSS co-cultured with MSCs exhibited significant improvement in locomotion, motor evoked potential, magnetic resonance imaging, diffusion tensor imaging, and urodynamic parameters. Meanwhile, nerve fibers were markedly improved in the CHSS adsorbed with MSCs group. Moreover, we observed that the implantation of CHSS combined with MSCs modulated inflammatory cytokine levels. Conclusions: The results preliminarily demonstrated that the transplantation of MSCs on a CHSS could improve the recovery of motor function after SCI. Thus, implanting the MSCs-laden CHSS is a promising combinatorial therapy for treatment in acute SCI.

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White matter regeneration induced by aligned fibrin nanofiber hydrogel contributes to motor functional recovery in canine T12 spinal cord injury

Regenerative Biomaterials ◽

10.1093/rb/rbab069 ◽

2021 ◽

Author(s):

Zheng Cao ◽

Weitao Man ◽

Yuhui Xiong ◽

Yi Guo ◽

Shuhui Yang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

White Matter ◽

Nerve Regeneration ◽

Spinal Cord Injuries ◽

Diffusion Tensor ◽

Nerve Fibers ◽

Functional Restoration ◽

Large Animal ◽

Cord Injury

Abstract A hierarchically aligned fibrin hydrogel (AFG) that possesses soft stiffness and aligned nanofiber structure has been successfully proven to facilitate neuroregeneration in vitro and in vivo. However, its potential in promoting nerve regeneration in large animal models that is critical for clinical translation has not been sufficiently specified. Here, the effects of AFG on directing neuroregeneration in canine hemisected T12 spinal cord injuries were explored. Histologically obvious white matter regeneration consisting of a large area of consecutive, compact, and aligned nerve fibers is induced by AFG, leading to a significant motor functional restoration. The canines with AFG implantation start to stand well with their defective legs from 3 to 4 weeks postoperatively and even effortlessly climb the steps from 7 to 8 weeks. Moreover, high-resolution multi-shot diffusion tensor imaging illustrates the spatiotemporal dynamics of nerve regeneration rapidly crossing the lesion within 4 weeks in the AFG group. Our findings indicate that AFG could be a potential therapeutic vehicle for spinal cord injury by inducing rapid white matter regeneration and restoring locomotion, pointing out its promising prospect in clinic practice.

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Nanoparticles guided precise transplantation of varying numbers of mesenchymal stem cells into post–traumatic syrinx in spinal cord injury rat

Bulletin of Russian State Medical University ◽

10.24075/brsmu.2018.084 ◽

2018 ◽

pp. 49-56

Author(s):

Chao Zhang ◽

A.Y. Morozova ◽

V.P. Baklaushev ◽

I.L. Gubsky ◽

P.A. Melnikov ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Magnetic Nanoparticles ◽

Diffusion Tensor ◽

Cell Number ◽

Functional Improvement ◽

Cord Injury ◽

Post Traumatic

Spinal cord injury (SCI) is a traumatic injury to the spinal cord which is not a consequence of the disease. Mesenchymal stem cells (MSCs) have gradually become one of the most used stem cells in research and clinic trial. Based on the previous reports employed the cells ranged from 4 • 105 to 1 • 106, the present study was performed to figure out the best number of MSCs for transplantation of the chronic SCI. Magnetic nanoparticles were used for proving the precise transplantation strategy. Using magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), diffusion tensor tractography (DTT), and behavior testing evaluations, we focused the effect of varying numbers of MSCs on reducing lesion cavity and post–traumatic syrinx formation, suppressing glial scar formation, enhancing neuronal fibers remodeling, promoting axonal regeneration and sprouting, improving vascularization, ameliorating the neuronal factors expressional level, and function improvement. Magnetic nanoparticles were precisely transplanted into the post–traumatic syrinx (PTS). MSCs can restore function after chronic SCI through stimulating the regeneration and sprouting of the axons, reducing the formation of PTS. The effect of MSCs on PTS management and functional improvement post chronic SCI was cell number–dependent, and within the range of 4 • 105 to 1 • 106, 1 • 106 cells were proved to be the best dose.

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Study on Application of Bone Marrow Mesenchymal Stem Cells Transplantation in Restorative Treatment of Spinal Cord Injury in Mice

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2404 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1122-1127

Author(s):

Yang Sun ◽

Zhongjing Jiang ◽

Hao Tang ◽

Jiang Xie

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Nerve Fibers ◽

Control Group ◽

Mouse Spinal Cord ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells

The spinal cord injury (SCI) refers to different degrees of injuries in the structure or function of spinal cord caused by different factors. The prevalence rate of SCI in the population under 40 years reaches 80%. SCI causes certain injury to both physiology and psychology of patients. An important factor leading to SCI is the rupture of nerve fibers. Bone marrow mesenchymal stem cells (BMMSCs) have the functions of inducing and supporting hematopoietic stem cells in bone marrow. In this study, SCI mouse model was established to assess the effect of BM-MSCs on SCI. A total of 30 SCI mouse model were established and assigned into transplantation group (15 mice) and control group (15 mice) according to random number table method. The mice in transplantation group were treated with BM-MSCs transplantation at SCI site, while mice in control group were treated with normal saline at SCI site. The bone marrow pathological changes were measured by HE staining and neural cells were assessed by Pischingert's methylene blue staining along with measuring SRY level by immunohistochemistry. The motor abilities of mice in transplantation group at the 2nd, 4th, 6th and 8th weeks were significantly higher than mice in control group (P < 0 05). A few vacuoles appeared in mice in transplantation group. The number of cells in mouse spinal cord tissues in transplantation group was increased significantly over time, but a large number of vacuoles appeared in mouse spinal cord tissues in control group with necrosis of a vast amount of nerve fibers (P < 0 05). The number and volume of Nissl bodies in mice in transplantation group was increased significantly at 2 weeks after treatment and degeneration status of nerve cells in transplantation group was significantly better than control group (P < 0 05). The SRY genes were expressed in transplantation group for a long term but not in control group (P < 0 05). The number of adherent cells increased significantly in transplantation group at 48 hours after treatment. BMMSCs transplantation can effectively promotes the recovery of SCI mice, indicating that it is worthy of clinical promotion and application.

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Electro-acupuncture promotes differentiation of mesenchymal stem cells, regeneration of nerve fibers and partial functional recovery after spinal cord injury

Experimental and Toxicologic Pathology ◽

10.1016/j.etp.2009.11.002 ◽

2011 ◽

Vol 63 (1-2) ◽

pp. 151-156 ◽

Cited By ~ 48

Author(s):

Qing Yan ◽

Jing-wen Ruan ◽

Ying Ding ◽

Wen-jie Li ◽

Yan Li ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Functional Recovery ◽

Nerve Fibers ◽

Cord Injury

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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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