Microglia Response and In Vivo Therapeutic Potential of Methylprednisolone-Loaded Dendrimer Nanoparticles in Spinal Cord Injury

Background/Aims: Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) promotes neural cell regeneration after spinal cord injury (SCI). Recently, we showed that suppression of microRNA-383 (miR-383) in MSCs increased the protein levels of glial cell line derived neurotrophic factor (GDNF), resulting in improved therapeutic effects on SCI. However, the overall effects of miR-383 suppression in MSCs on SCI therapy were not determined yet. Here, we addressed this question. Methods: We used bioinformatics tools to predict all miR-383-targeting genes, confirmed the functional bindings in a dual luciferase reporter assay. The effects of alteration of candidate genes in MSCs on cell proliferation were analyzed by MTT assay and by Western blotting for PCNA. The effects on angiogenesis were assessed by HUVEC assay. The effects on SCI in vivo were analyzed by transplantation of the modified MSCs into nude rats that underwent SCI. Results: Suppression of miR-383 in MSCs not only upregulated GDNF protein, but also increased vascular endothelial growth factor A (VEGF-A) and cyclin-dependent kinase 19 (CDK19), two other miR-383 targets. MiR-383-suppression-induced increases in CDK19 resulted in a slight but significant increase in MSC proliferation, while miR-383-suppression-induced increases in VEGF-A resulted in a slight but significant increase in MSC-mediated angiogenesis. Conclusions: Upregulation of CDK19 and VEGF-A by miR-383 suppression in MSCs further improve the therapeutic potential of MSCs in treating SCI in rats.

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Bazedoxifene, a Selective Estrogen Receptor Modulator, Promotes Functional Recovery in a Spinal Cord Injury Rat Model

International Journal of Molecular Sciences ◽

10.3390/ijms222011012 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11012

Author(s):

Yiyoung Kim ◽

Eun Ji Roh ◽

Hari Prasad Joshi ◽

Hae Eun Shin ◽

Hyemin Choi ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Therapeutic Potential ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Sprague Dawley ◽

Post Injury ◽

Static Compression ◽

Cord Injury

In research on various central nervous system injuries, bazedoxifene acetate (BZA) has shown two main effects: neuroprotection by suppressing the inflammatory response and remyelination by enhancing oligodendrocyte precursor cell differentiation and oligodendrocyte proliferation. We examined the effects of BZA in a rat spinal cord injury (SCI) model. Anti-inflammatory and anti-apoptotic effects were investigated in RAW 264.7 cells, and blood-spinal cord barrier (BSCB) permeability and angiogenesis were evaluated in a human brain endothelial cell line (hCMEC/D3). In vivo experiments were carried out on female Sprague Dawley rats subjected to moderate static compression SCI. The rats were intraperitoneally injected with either vehicle or BZA (1mg/kg pre-SCI and 3mg/kg for 7 days post-SCI) daily. BZA decreased the lipopolysaccharide-induced production of proinflammatory cytokines and nitric oxide in RAW 264.7 cells and preserved BSCB disruption in hCMEC/D3 cells. In the rats, BZA reduced caspase-3 activity at 1 day post-injury (dpi) and suppressed phosphorylation of MAPK (p38 and ERK) at dpi 2, hence reducing the expression of IL-6, a proinflammatory cytokine. BZA also led to remyelination at dpi 20. BZA contributed to improvements in locomotor recovery after compressive SCI. This evidence suggests that BZA may have therapeutic potential to promote neuroprotection, remyelination, and functional outcomes following SCI.

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Neural Stem Cell-Conditioned Medium Suppresses Inflammation and Promotes Spinal Cord Injury Recovery

Cell Transplantation ◽

10.3727/096368916x693473 ◽

2017 ◽

Vol 26 (3) ◽

pp. 469-482 ◽

Cited By ~ 18

Author(s):

Zhijian Cheng ◽

Dale B. Bosco ◽

Li Sun ◽

Xiaoming Chen ◽

Yunsheng Xu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Conditioned Medium ◽

Neural Stem Cell ◽

Therapeutic Potential ◽

Secondary Injury ◽

Cord Injury

Spinal cord injury (SCI) causes functional impairment as a result of the initial injury followed by secondary injury mechanism. SCI provokes an inflammatory response that causes secondary tissue damage and neurodegeneration. While the use of neural stem cell (NSC) engraftment to mitigate secondary injury has been of interest to many researchers, it still faces several limitations. As such, we investigated if NSC-conditioned medium (NSC-M) possesses therapeutic potential for the treatment of SCI. It has been proposed that many of the beneficial effects attributed to stem cell therapies are due to secreted factors. Utilizing primary cell culture and murine models of SCI, we determined that systemic treatment with NSC-M was able to significantly improve motor function and lesion healing. In addition, NSC-M demonstrated significant anti-inflammatory potential in vitro and in vivo, reducing inflammatory cytokine expression in both activated macrophages and injured spinal cord tissues. NSC-M was also able to reduce the expression of inducible nitric oxide synthase (iNOS) within the spleen of injured animals, indicating an ability to reduce systemic inflammation. Thus, we believe that NSC-M offers a possible alternative to direct stem cell engraftment for the treatment of SCI.

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Microglia Response and In Vivo Therapeutic Potential of Methylprednisolone-Loaded Dendrimer Nanoparticles in Spinal Cord Injury

Small ◽

10.1002/smll.201201888 ◽

2012 ◽

Vol 9 (5) ◽

pp. 738-749 ◽

Cited By ~ 63

Author(s):

Susana R. Cerqueira ◽

Joaquim M. Oliveira ◽

Nuno A. Silva ◽

Hugo Leite-Almeida ◽

Silvina Ribeiro-Samy ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Therapeutic Potential ◽

Cord Injury

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Therapeutic Potential of Niche-Specific Mesenchymal Stromal Cells for Spinal Cord Injury Repair

Cells ◽

10.3390/cells10040901 ◽

2021 ◽

Vol 10 (4) ◽

pp. 901

Author(s):

Susan L. Lindsay ◽

Susan C. Barnett

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stromal Cells ◽

Therapeutic Strategy ◽

Therapeutic Potential ◽

Ex Vivo ◽

Biological Properties ◽

Cord Injury

The use of mesenchymal stem/stromal cells (MSCs) for transplant-mediated repair represents an important and promising therapeutic strategy after spinal cord injury (SCI). The appeal of MSCs has been fuelled by their ease of isolation, immunosuppressive properties, and low immunogenicity, alongside the large variety of available tissue sources. However, despite reported similarities in vitro, MSCs sourced from distinct tissues may not have comparable biological properties in vivo. There is accumulating evidence that stemness, plasticity, immunogenicity, and adaptability of stem cells is largely controlled by tissue niche. The extrinsic impact of cellular niche for MSC repair potential is therefore important, not least because of its impact on ex vivo expansion for therapeutic purposes. It is likely certain niche-targeted MSCs are more suited for SCI transplant-mediated repair due to their intrinsic capabilities, such as inherent neurogenic properties. In addition, the various MSC anatomical locations means that differences in harvest and culture procedures can make cross-comparison of pre-clinical data difficult. Since a clinical grade MSC product is inextricably linked with its manufacture, it is imperative that cells can be made relatively easily using appropriate materials. We discuss these issues and highlight the importance of identifying the appropriate niche-specific MSC type for SCI repair.

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Faculty Opinions recommendation of Effect of vascular endothelial growth factor treatment in experimental traumatic spinal cord injury: in vivo longitudinal assessment.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.9908956.11172056 ◽

2011 ◽

Author(s):

Jose V Lafuente ◽

Enrike Argandoña

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Vascular Endothelial Growth Factor ◽

Traumatic Spinal Cord Injury ◽

Vascular Endothelial ◽

Longitudinal Assessment ◽

Cord Injury ◽

Endothelial Growth Factor ◽

Growth Factor Treatment

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Stem Cell Transplantation: A Promising Therapy for Spinal Cord Injury

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190823144424 ◽

2020 ◽

Vol 15 (4) ◽

pp. 321-331 ◽

Cited By ~ 2

Author(s):

Zhe Gong ◽

Kaishun Xia ◽

Ankai Xu ◽

Chao Yu ◽

Chenggui Wang ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Therapeutic Potential ◽

Embryonic Stem ◽

Current Status ◽

Cord Injury

Spinal Cord Injury (SCI) causes irreversible functional loss of the affected population. The incidence of SCI keeps increasing, resulting in huge burden on the society. The pathogenesis of SCI involves neuron death and exotic reaction, which could impede neuron regeneration. In clinic, the limited regenerative capacity of endogenous cells after SCI is a major problem. Recent studies have demonstrated that a variety of stem cells such as induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and Neural Progenitor Cells (NPCs) /Neural Stem Cells (NSCs) have therapeutic potential for SCI. However, the efficacy and safety of these stem cellbased therapy for SCI remain controversial. In this review, we introduce the pathogenesis of SCI, summarize the current status of the application of these stem cells in SCI repair, and discuss possible mechanisms responsible for functional recovery of SCI after stem cell transplantation. Finally, we highlight several areas for further exploitation of stem cells as a promising regenerative therapy of SCI.

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A Collagen-Based Scaffold for Promoting Neural Plasticity in a Rat Model of Spinal Cord Injury

Polymers ◽

10.3390/polym12102245 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2245

Author(s):

Jue-Zong Yeh ◽

Ding-Han Wang ◽

Juin-Hong Cherng ◽

Yi-Wen Wang ◽

Gang-Yi Fan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Neural Plasticity ◽

Collagen Scaffold ◽

Glial Scar ◽

Beneficial Effects ◽

Cord Injury

In spinal cord injury (SCI) therapy, glial scarring formed by activated astrocytes is a primary problem that needs to be solved to enhance axonal regeneration. In this study, we developed and used a collagen scaffold for glial scar replacement to create an appropriate environment in an SCI rat model and determined whether neural plasticity can be manipulated using this approach. We used four experimental groups, as follows: SCI-collagen scaffold, SCI control, normal spinal cord-collagen scaffold, and normal control. The collagen scaffold showed excellent in vitro and in vivo biocompatibility. Immunofluorescence staining revealed increased expression of neurofilament and fibronectin and reduced expression of glial fibrillary acidic protein and anti-chondroitin sulfate in the collagen scaffold-treated SCI rats at 1 and 4 weeks post-implantation compared with that in untreated SCI control. This indicates that the collagen scaffold implantation promoted neuronal survival and axonal growth within the injured site and prevented glial scar formation by controlling astrocyte production for their normal functioning. Our study highlights the feasibility of using the collagen scaffold in SCI repair. The collagen scaffold was found to exert beneficial effects on neuronal activity and may help in manipulating synaptic plasticity, implying its great potential for clinical application in SCI.

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