scholarly journals Glial Bridge Ecology: Cellular Mechanisms that Drive Spinal Cord Regeneration in Zebrafish

2018 ◽  
Author(s):  
Corbin J. Schuster ◽  
Robert M. Kao
Keyword(s):  
Spinal Cord ◽  
Molecular Mechanisms ◽  
Cell Injury ◽  
Model Organism ◽  
Spinal Cord Regeneration ◽  
Cellular Mechanisms ◽  
Bridge Formation ◽  
Cellular Processes ◽  
Cord Injury ◽  
One Step

Zebrafish have been found to be the premier model organism in biological and biomedical research, specifically offering many advantages in developmental biology and genetics. This unique aquatic species has been found to have the capacity to regenerate their spinal cord after injury. However, the complete molecular and cellular mechanisms behind glial bridge formation in the central and peripheral nervous systems upon glial cell injury remains unclear. This review paper focuses on the molecular mechanisms and cellular processes that underlie spinal cord regeneration in four initial phases: proliferation and initial migration; migration and differentiation; glial bridge formation; and remodeling. We propose that within these four phases the cellular mechanisms that underlie spinal cord regeneration each express a terminating signal that aborts one step of the process and initiates the next. Specifically, future studies would be devoted to investigate transmitting signals in the spinal cord injury micro-environment in hope to contribute to the understanding of underlying cellular mechanisms by connecting each process of spinal cord regeneration in zebrafish.

scholarly journals The Organotypic Longitudinal Spinal Cord Slice Culture for Stem Cell Study

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Joanna Sypecka ◽  
Sylwia Koniusz ◽  
Maria Kawalec ◽  
Anna Sarnowska
Keyword(s):  
Spinal Cord ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Scientific Basis ◽  
Slice Culture ◽  
Spinal Cord Regeneration ◽  
Spinal Cord Slice ◽  
Detailed Method ◽  
Cord Injury

The objective of this paper is to describe in detail the method of organotypic longitudinal spinal cord slice culture and the scientific basis for its potential utility. The technique is based on the interface method, which was described previously and thereafter was modified in our laboratory. The most important advantage of the presented model is the preservation of the intrinsic spinal cord fiber tract and the ventrodorsal polarity of the spinal cord. All the processes occurring during axonal growth, regeneration, synapse formation, and myelination could be visualized while being culturedin vitrofor up to 4-5 weeks after the slices had been isolated. Both pups and adult animals can undergo the same, equally efficient procedures when going by the protocol in question. The urgent need for an appropriatein vitromodel for spinal cord regeneration results from a greater number of clinical trials concerning regenerative medicine in the spinal cord injury and from still insufficient knowledge of the molecular mechanisms involved in the neuroreparative processes. The detailed method of organotypic longitudinal spinal cord slice culture is accompanied by examples of its application to studying biological processes to which both the CNS inhabiting and grafted cells are subjected.

scholarly journals GAS5 knockdown alleviates spinal cord injury by reducing VAV1 expression via RNA binding protein CELF2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dan Wang ◽  
Xiaoxiao Xu ◽  
Junwei Pan ◽  
Shixin Zhao ◽  
Yu Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Cell Injury ◽  
Glucose Deprivation ◽  
Nucleotide Exchange ◽  
Coding Region ◽  
Cord Injury

AbstractLong non-coding RNA growth arrest specific transcript 5 (GAS5) has been found to be implicated in the pathogenesis of central nervous diseases and to be a contributor to hypoxic brain injury. However, the roles and molecular mechanisms of GAS5 in spinal cord injury (SCI) have not thoroughly investigated. Here, we reported that GAS5 knockdown improved rat locomotor function and alleviated pathological damage of spinal cord tissues by reducing oxidative stress, caspase-3 activity and vav guanine nucleotide exchange factor 1 (VAV1) expression in SCI rat models. GAS5 knockdown inhibited the increase of malondialdehyde (MDA) level and cell apoptotic rate induced by oxygen–glucose deprivation (OGD) and weakened the inhibitory effects of OGD on superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and cell viability in RN-Sc cells, suggesting that GAS5 loss mitigated OGD-triggered oxidative stress and cell injury in RN-Sc cells. Molecular mechanism explorations revealed that GAS5 recruited CUGBP, Elav-like family member 2 (CELF2) to the coding region of VAV1 mRNA, resulting in the increase of VAV1 mRNA stability and expression levels. VAV1 knockdown weakened OGD-induced oxidative stress and cell injury in RN-Sc cells. VAV1 loss alleviated GAS5-induced oxidative stress and cell injury in OGD-treated RN-Sc cells. As a conclusion, our findings suggested that GAS5 aggravated SCI by increasing VAV1 expression via binding with CELF2, deepening our understanding on function and molecular basis of GAS5 in SCI.

Mechanisms leading to restoration of muscle size with exercise and transplantation after spinal cord injury

2000 ◽  
Vol 279 (6) ◽  
pp. C1677-C1684 ◽  
Author(s):  
Esther E. Dupont-Versteegden ◽  
René J. L. Murphy ◽  
John D. Houlé ◽  
Cathy M. Gurley ◽  
Charlotte A. Peterson
Keyword(s):  
Spinal Cord ◽  
Satellite Cell ◽  
Fiber Type ◽  
Cell Activity ◽  
Muscle Size ◽  
Spinal Cord Tissue ◽  
Cellular Mechanisms ◽  
Cross Sectional ◽  
Cord Injury ◽  
Nuclear Number

We have shown that cycling exercise combined with fetal spinal cord transplantation restored muscle mass reduced as a result of complete transection of the spinal cord. In this study, mechanisms whereby this combined intervention increased the size of atrophied soleus and plantaris muscles were investigated. Rats were divided into five groups ( n = 4, per group): control, nontransected; spinal cord transected at T10 for 8 wk (Tx); spinal cord transected for 8 wk and exercised for the last 4 wk (TxEx); spinal cord transected for 8 wk with transplantation of fetal spinal cord tissue into the lesion site 4 wk prior to death (TxTp); and spinal cord transected for 8 wk, exercised for the last 4 wk combined with transplantation 4 wk prior to death (TxExTp). Tx soleus and plantaris muscles were decreased in size compared with control. Exercise and transplantation alone did not restore muscle size in soleus, but exercise alone minimized atrophy in plantaris. However, the combination of exercise and transplantation resulted in a significant increase in muscle size in soleus and plantaris compared with transection alone. Furthermore, myofiber nuclear number of soleus was decreased by 40% in Tx and was not affected in TxEx or TxTp but was restored in TxExTp. A strong correlation ( r = 0.85) between myofiber cross-sectional area and myofiber nuclear number was observed in soleus, but not in plantaris muscle, in which myonuclear number did not change with any of the experimental manipulations. 5′-Bromo-2′-deoxyuridine-positive nuclei inside the myofiber membrane were observed in TxExTp soleus muscles, indicating that satellite cells had divided and subsequently fused into myofibers, contributing to the increase in myonuclear number. The increase in satellite cell activity did not appear to be controlled by the insulin-like growth factors (IGF), as IGF-I and IGF-II mRNA abundance was decreased in Tx soleus and plantaris, and was not restored with the interventions. These results indicate that, following a relatively long postinjury interval, exercise and transplantation combined restore muscle size. Satellite cell fusion and restoration of myofiber nuclear number contributed to increased muscle size in the soleus, but not in plantaris, suggesting that cellular mechanisms regulating muscle size differ between muscles with different fiber type composition.

scholarly journals Olfactory bulb transplantation in complete spinal cord injury: axonal regeneration and locomotor recovery

2015 ◽  
Vol 14 (1) ◽  
pp. 50-52
Author(s):  
Carlos Abraham Arellanes-Chávez ◽  
Ariana Martínez Bojórquez ◽  
Ernesto Ramos Martínez
Keyword(s):  
Spinal Cord ◽  
Axonal Regeneration ◽  
Sufficient Evidence ◽  
Spinal Cord Regeneration ◽  
Sprague Dawley ◽  
Locomotor Recovery ◽  
Randomized Controlled ◽  
Sprague Dawley Rats ◽  
Cord Injury ◽  
Complete Spinal Cord Injury

OBJECTIVES: To determine whether the intervention in rats is effective in terms of spinal cord regeneration and locomotor recovery, in order to obtain sufficient evidence to apply the therapy in humans. METHODS: a randomized, controlled, experimental, prospective, randomized trial was conducted, with a sample of 15 adult female Sprague-Dawley rats weighing 250 gr. They were divided into three equal groups, and trained for 2 weeks based on Pavlov's classical conditioning method, to strengthen the muscles of the 4 legs, stimulate the rats mentally, and keep them healthy for the surgery. RESULTS: It was observed that implantation of these cells into the site of injury may be beneficial to the process of spinal cord regeneration after spinal trauma, to mediate secretion of neurotrophic and neuroprotective chemokines, and that the OECs have the ability to bridge the repair site and decrease the formation of gliosis, creating a favorable environment for axonal regeneration. CONCLUSION: It is emphasized that the olfactory ensheathing glial cells possess unique regenerative properties; however, it was not until recently that the activity of promoting central nervous system regeneration was recognized.

scholarly journals Lipocalin 2 as Putative Modulator of Local Inflammatory Processes in the Spinal Cord and Component of Organ Cross-talk After Spinal Cord Injury

2021 ◽  
Author(s):  
Victoria Behrens ◽  
Clara Voelz ◽  
Nina Müller ◽  
Weiyi Zhao ◽  
Tim Clarner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Blood Serum ◽  
Negative Influence ◽  
Lipocalin 2 ◽  
Cellular Processes ◽  
Cord Injury ◽  
Inflammatory Processes ◽  
Underlying Mechanisms ◽  
Sites Of Action

Abstract Lipocalin 2 (Lcn2), an immunomodulator, regulates various cellular processes such as iron transport and defense against bacterial infection. Under pathological conditions, Lcn2 promotes neuroinflammation via the recruitment and activation of immune cells and glia, particularly microglia and astrocytes. Although it seems to have a negative influence on the functional outcome in spinal cord injury (SCI), the extent of its involvement in SCI and the underlying mechanisms are not yet fully known. In this study, using a SCI contusion mouse model, we first investigated the expression pattern of Lcn2 in different parts of the CNS (spinal cord and brain), blood serum and in the liver. Interestingly, we could note a significant increase in Lcn2 throughout the whole spinal cord, in the brain, liver and in blood serum. This demonstrates the diversity of its possible sites of action in SCI. Further, genetic deficiency of Lcn2 (Lcn2-/-) significantly reduced certain aspects of gliosis in the SCI-mice. Taken together, our studies provide first valuable hints, suggesting that Lcn2 is involved in the local and systemic effects post SCI, and might modulate the impairment of different peripheral organs after injury.

Abstract 497: Cholesterol and Toll-like Receptor Signaling Are Important Regulators of Macrophage Interactions with Atherosclerotic Lipoprotein Aggregates

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Harvey F Chin ◽  
Abigail Haka ◽  
Frederick R Maxfield
Keyword(s):  
Molecular Mechanisms ◽  
Atherosclerotic Plaques ◽  
Cholesteryl Esters ◽  
Cellular Mechanisms ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Atherosclerotic Plaque Formation ◽  
Subendothelial Space ◽  
Morphological Responses ◽  
Cytoskeletal Rearrangements

Macrophages encounter deposits of aggregated low-density lipoproteins (agLDL) in the subendothelial space of blood vessels during the first stages of atherosclerotic plaque formation. Notably, current models for the mechanism of macrophage internalization of cholesterol in early atherosclerotic plaques are incomplete due to the lack of attention paid to the unique cellular mechanisms that are required for macrophages to degrade aggregates of LDL in particular, which can comprise >90% of the LDL in atherosclerotic plaques. In fact, internalization of cholesterol from cholesteryl esters in agLDL involves the development of intriguing cellular processes in which extracellular acidic compartments, lysosomal synapses (LSs), are formed whereby agLDL is partially degraded prior to internalization. This process requires extensive cytoskeletal rearrangements and secretion of lysosomal enzymes responsible for hydrolysis of cholesteryl esters from the agLDL. Subsequent delivery of free cholesterol from agLDL to the macrophage plasma membrane is central for development of the LS. Nonetheless, the molecular mechanism underlying initiation and propagation of the LS are currently largely unknown. This research proposal aims to elucidate the molecular mechanisms of LS formation and the role that cholesterol plays in eliciting these morphological responses to agLDL. Fluorescence microscopy assays were used to identify activation of TLR4 and downstream signaling involving PI3K and Akt as important events leading to LS formation. Furthermore, morphological responses of macrophages to cholesterol overloading require overlapping signaling pathways, indicating the role of interplay of cholesterol and TLR4 signaling in development of this novel macrophage interaction with aggregated LDL found in plaques. Identification of specific molecular pathways involved in this process will not only contribute to the basic understanding of one of the primary cellular processes contributing to atherosclerosis, one of the primary causes of heart disease, but also provide tangible molecular targets for the ultimate development of therapies.

Activation of SIRT1 by Hyperbaric  Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

2020 ◽  
Author(s):  
Huiqiang Chen ◽  
Mengyu Yao ◽  
Zhibo Li ◽  
Ranran Xing ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Hyperbaric Oxygenation ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Sprague Dawley ◽  
Inflammatory Cascade ◽  
Locomotor Function ◽  
Cord Injury

Abstract Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

scholarly journals Regenerative therapy for spinal cord injury using iPSC technology

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Narihito Nagoshi ◽  
Hideyuki Okano ◽  
Masaya Nakamura
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Chronic Phase ◽  
Regenerative Therapy ◽  
Spinal Cord Regeneration ◽  
Gamma Secretase ◽  
Safety Issues ◽  
Beneficial Effects ◽  
Cord Injury ◽  
Induced Pluripotent

Abstract Spinal cord injury (SCI) is a devastating event that causes permanent neurologic impairments. Cell transplantation therapy using neural precursor cells (NPCs) is a promising intervention aiming to replace damaged neural tissue and restore certain functions. Because the protocol to produce human induced pluripotent stem cells (iPSCs) was first established, we have attempted to apply this technology for regenerative therapy in SCI. Our group reported beneficial effects of iPSC-derived NPC transplantation and addressed safety issues on tumorigenicity after grafting. These findings will soon be tested at the clinical trial stage, the protocol of which has already been approved by the Ministry of Health, Labour and Welfare in Japan. Current transplantation therapies treat patients at the subacute phase after injury, highlighting the need for effective treatments for chronic SCI. We recently demonstrated the modest efficacy of gamma secretase inhibitor treatment of iPSC-NPCs before transplantation at the chronic phase. However, more comprehensive strategies involving combinatory therapies are essential to enhance current spinal cord regeneration treatments.

Cellular Dynamics during Spinal Cord Regeneration in Larval Zebrafish

2019 ◽  
Vol 41 (1-2) ◽  
pp. 112-122 ◽  
Author(s):  
Consuelo Anguita-Salinas ◽  
Mario Sánchez ◽  
Rodrigo A. Morales ◽  
María Laura Ceci ◽  
Diego Rojas-Benítez ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Immune Cells ◽  
Cell Types ◽  
Regenerative Process ◽  
Spinal Cord Regeneration ◽  
Cord Injury ◽  
Complete Reversal ◽  
Transgenic Lines ◽  
Functional Regeneration

The study of spinal cord regeneration using diverse animal models, which range from null to robust regenerative capabilities, is imperative for understanding how regeneration evolved and, eventually, to treat spinal cord injury and paralysis in humans. In this study, we used electroablation to fully transect the spinal cord of zebrafish larvae (3 days postfertilization) and examined regeneration of the tissue over time. We used transgenic lines to follow immune cells, oligodendrocytes, and neurons in vivo during the entire regenerative process. We observed that immune cells are recruited to the injury site, oligodendrocytes progenitor cells (olig2-expressing cells) invade, and axons cross the gap generated upon damage from anterior to reinnervate caudal structures. Together with the recovery of cell types and structures, a complete reversal of paralysis was observed in the lesioned larvae indicating functional regeneration. Finally, using transplantation to obtain mosaic larvae with single-labeled neurons, we show that severed spinal axons exhibited varying regenerative capabilities and plasticity depending on their original dorsoventral position in the spinal cord.

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