Ecto-domain phosphorylation promotes functional recovery from spinal cord injury

Abstract Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP.

Download Full-text

An In Vitro Comparison of the Neurotrophic and Angiogenic Activity of Human and Canine Adipose-Derived Mesenchymal Stem Cells (MSCs): Translating MSC-Based Therapies for Spinal Cord Injury

Biomolecules ◽

10.3390/biom10091301 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1301

Author(s):

Ibtesam R. T. Al Delfi ◽

Chelsea R. Wood ◽

Louis D. V. Johnson ◽

Martyn D. Snow ◽

John F. Innes ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Proliferation ◽

Endothelial Cell ◽

Neuronal Cell ◽

Endothelial Cell Migration ◽

Differentiation Potential ◽

Angiogenic Activity ◽

Cord Injury

The majority of research into the effects of mesenchymal stem cell (MSC) transplants on spinal cord injury (SCI) is performed in rodent models, which may help inform on mechanisms of action, but does not represent the scale and wound heterogeneity seen in human SCI. In contrast, SCI in dogs occurs naturally, is more akin to human SCI, and can be used to help address important aspects of the development of human MSC-based therapies. To enable translation to the clinic and comparison across species, we have examined the paracrine, regenerative capacity of human and canine adipose-derived MSCs in vitro. MSCs were initially phenotyped according to tissue culture plastic adherence, cluster of differentiation (CD) immunoprofiling and tri-lineage differentiation potential. Conditioned medium (CM) from MSC cultures was then assessed for its neurotrophic and angiogenic activity using established cell-based assays. MSC CM significantly increased neuronal cell proliferation, neurite outgrowth, and βIII tubulin immunopositivity. In addition, MSC CM significantly increased endothelial cell migration, cell proliferation and the formation of tubule-like structures in Matrigel assays. There were no marked or significant differences in the capacity of human or canine MSC CM to stimulate neuronal cell or endothelial cell activity. Hence, this study supports the use of MSC transplants for canine SCI; furthermore, it increases understanding of how this may subsequently provide useful information and translate to MSC transplants for human SCI.

Download Full-text

Circ-Ctnnb1 regulates neuronal injury in spinal cord injury through Wnt/β-catenin signaling pathway

Developmental Neuroscience ◽

10.1159/000521172 ◽

2021 ◽

Author(s):

Jialong Qi ◽

Tao Wang ◽

Zhidong Zhang ◽

Zongsheng Yin ◽

Yiming Liu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signaling Pathway ◽

Rat Model ◽

Cell Model ◽

Neuronal Cells ◽

Neuronal Cell ◽

Cord Injury

Study design: Spinal cord injury (SCI) rat model and cell model were established for in vivo and in vitro experiments. Functional assays were utilized to explore the role of the circRNAs derived from catenin beta 1 (mmu_circ_0001859, circ-Ctnnb1 herein) in regulating neuronal cell viability and apoptosis. Bioinformatics analysis and mechanism experiments were conducted to assess the underlying molecular mechanism of circ-Ctnnb1. Objective: We aimed to probe into the biological function of circ-Ctnnb1 in neuronal cells of SCI. Methods: The rat model of SCI and hypoxia-induced cell model were constructed to examine circ-Ctnnb1 expression in SCI through quantitative reverse transcription real-time polymerase chain reaction (RT-qPCR). Basso, Beattie and Bresnahan (BBB) score was utilized for evaluating the neurological function. Terminal-deoxynucleoitidyl Transferase Mediated Nick End labeling (TUNEL) assays were performed to assess the apoptosis of neuronal cells. RNase R and Actinomycin D (ActD) were used to treat cells to evaluate the stability of circ-Ctnnb1. Results: Circ-Ctnnb1 was highly expressed in SCI rat models and hypoxia-induced neuronal cells, and its deletion elevated the apoptosis rate of hypoxia-induced neuronal cells. Furthermore, circ-Ctnnb1 activated the Wnt/β-catenin signaling pathway via sponging mircoRNA-205-5p (miR-205-5p) to up-regulate Ctnnb1 and Wnt family member 2B (Wnt2b). Conclusion: Circ-Ctnnb1 promotes SCI through regulating Wnt/β-catenin signaling via modulating the miR-205-5p/Ctnnb1/Wnt2b axis.

Download Full-text

A meta-analysis of exosome in the treatment of spinal cord injury

Open Medicine ◽

10.1515/med-2021-0304 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1043-1060

Author(s):

Hanxiao Yi ◽

Yang Wang

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Sequential Analysis ◽

Meta Analysis ◽

Cochrane Library ◽

Trial Sequential Analysis ◽

Therapeutic Effects ◽

Locomotor Function ◽

Cord Injury

Abstract Context There are no recommended therapeutic agents for acute spinal cord injury (SCI) due to the pathophysiological complexity of the injury. Objective The objective of this study is to investigate the efficacy of various exosomes and potential factors impacting the efficacy of exosomes. Methods We searched the PubMed, EMBASE, Web of Science, Medline, Scopus, and Cochrane Library databases to systematically collect articles comparing the locomotor function of SCI rodents undergoing exosome treatment and untreated SCI rodents. No language was preferred. Results Pooled analysis revealed that the locomotor function recovery of SCI rodents receiving exosomes was greatly improved (583 rats, 3.12, 95% CI: 2.56–3.67, p < 0.01; 116 mice, 2.46, 95% CI: 1.20–3.72, p < 0.01) compared to those of control rodents. The trial sequential analysis demonstrated the findings of the meta-analysis with the cumulative Z-curve crossing the upper monitoring boundary for the benefit and reaching the adjusted required information size. However, the origin of the exosome, SCI model, and administration method determined the therapeutic effect to some extent. Conclusions Despite the proven therapeutic effects of exosomes on SCI rodents, the results should be interpreted cautiously considering the diversity in vivo and in vitro in relation to future trials.

Download Full-text

Neural Stem Cell Transplantation Improves Locomotor Function in Spinal Cord Transection Rats Associated with Nerve Regeneration and IGF-1 R Expression

Cell Transplantation ◽

10.1177/0963689719860128 ◽

2019 ◽

Vol 28 (9-10) ◽

pp. 1197-1211 ◽

Cited By ~ 4

Author(s):

Xiao-Ming Zhao ◽

Xiu-Ying He ◽

Jia Liu ◽

Yang Xu ◽

Fei-Fei Xu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Function ◽

Spinal Nerve ◽

Nerve Fibers ◽

Spinal Cord Transection ◽

Type I ◽

Locomotor Function ◽

Cord Injury

Transplantation of neural stem cells (NSCs) is a potential strategy for the treatment of spinal cord transection (SCT). Here we investigated whether transplanted NSCs would improve motor function of rats with SCT and explored the underlying mechanism. First, the rats were divided into sham, SCT, and NSC groups. Rats in the SCT and NSC groups were all subjected to SCT in T10, and were administered with media and NSC transplantation into the lesion site, respectively. Immunohistochemistry was used to label Nestin-, TUNEL-, and NeuN-positive cells and reveal the expression and location of type I insulin-like growth factor receptor (IGF-1 R). Locomotor function of hind limbs was assessed by Basso, Beattie, Bresnahan (BBB) score and inclined plane test. The conduction velocity and amplitude of spinal nerve fibers were measured by electrophysiology and the anatomical changes were measured using magnetic resonance imaging. Moreover, expression of IGF-1 R was determined by real-time polymerase chain reaction and Western blotting. The results showed that NSCs could survive and differentiate into neurons in vitro and in vivo. SCT-induced deficits were reduced by NSC transplantation, including increase in NeuN-positive cells and decrease in apoptotic cells. Moreover, neurophysiological profiles indicated that the latent period was decreased and the peak-to-peak amplitude of spinal nerve fibers conduction was increased in transplanted rats, while morphological measures indicated that fractional anisotropy and the number of nerve fibers in the site of spinal cord injury were increased after NSC transplantation. In addition, mRNA and protein level of IGF-1 R were increased in the rostral segment in the NSC group, especially in neurons. Therefore, we concluded that NSC transplantation promotes motor function improvement of SCT, which might be associated with activated IGF-1 R, especially in the rostral site. All of the above suggests that this approach has potential for clinical treatment of spinal cord injury.

Download Full-text

β 2-Adrenoreceptor Agonist-Enhanced Recovery of Locomotor Function after Spinal Cord Injury Is Glutathione Dependent

Journal of Neurotrauma ◽

10.1089/neu.2006.23.170 ◽

2006 ◽

Vol 23 (2) ◽

pp. 170-180 ◽

Cited By ~ 14

Author(s):

Richard J. Zeman ◽

Hong Peng ◽

Yong Feng ◽

Hua Song ◽

Xiaoping Liu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Enhanced Recovery ◽

Locomotor Function ◽

Cord Injury

Download Full-text

Faculty Opinions recommendation of Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.

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

10.3410/f.1001592.11054 ◽

2001 ◽

Author(s):

Marie Filbin

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Dorsal Column ◽

Lesion Site ◽

Cord Injury ◽

Adult Spinal Cord

Download Full-text

Knockdown of long non-coding RNA LEF1-AS1 attenuates apoptosis and inflammatory injury of microglia cells following spinal cord injury

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-020-02041-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Sheng-Yu Cui ◽

Wei Zhang ◽

Zhi-Ming Cui ◽

Hong Yi ◽

Da-Wei Xu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Viability ◽

Microglial Cells ◽

Protective Effects ◽

Loss Of Function ◽

Sprague Dawley ◽

Cord Injury ◽

Apoptosis And Inflammation

Abstract Background Spinal cord injury (SCI) is associated with health burden both at personal and societal levels. Recent assessments on the role of lncRNAs in SCI regulation have matured. Therefore, to comprehensively explore the function of lncRNA LEF1-AS1 in SCI, there is an urgent need to understand its occurrence and development. Methods Using in vitro experiments, we used lipopolysaccharide (LPS) to treat and establish the SCI model primarily on microglial cells. Gain- and loss of function assays of LEF1-AS1 and miR-222-5p were conducted. Cell viability and apoptosis of microglial cells were assessed via CCK8 assay and flow cytometry, respectively. Adult Sprague-Dawley (SD) rats were randomly divided into four groups: Control, SCI, sh-NC, and sh-LEF-AS1 groups. ELISA test was used to determine the expression of TNF-α and IL-6, whereas the protein level of apoptotic-related markers (Bcl-2, Bax, and cleaved caspase-3) was assessed using Western blot technique. Results We revealed that LncRNA LEF1-AS1 was distinctly upregulated, whereas miR-222-5p was significantly downregulated in LPS-treated SCI and microglial cells. However, LEF1-AS1 knockdown enhanced cell viability, inhibited apoptosis, as well as inflammation of LPS-mediated microglial cells. On the contrary, miR-222-5p upregulation decreased cell viability, promoted apoptosis, and inflammation of microglial cells. Mechanistically, LEF1-AS1 served as a competitive endogenous RNA (ceRNA) by sponging miR-222-5p, targeting RAMP3. RAMP3 overexpression attenuated LEF1-AS1-mediated protective effects on LPS-mediated microglial cells from apoptosis and inflammation. Conclusion In summary, these findings ascertain that knockdown of LEF1-AS1 impedes SCI progression via the miR-222-5p/RAMP3 axis.

Download Full-text

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.

Download Full-text