Smad Interacting Protein-1 is Essential for Oligodendrocyte Differentiation

Abstract Precursor/stem cell substitutive therapy to promote remyelination is an ideal strategy for central nervous system demyelinating diseases such as spinal cord injury (SCI). However, the microenvironment of the injured area is not conducive to the survival, differentiation, and functions of the transplanted cells. Identifying and regulating the key inhibitory factors might be an important target for the treatment of demyelinating diseases. Smad interacting protein-1 (Sip1) is a transcription factor that binds to phosphorylated R-Smad in the nucleus, which promotes remyelination by inducing the differentiation of oligodendrocytes. In this study, we show that the expression of Sip1 is up-regulated and peaks by 1 day and then returns to normal levels 7 days after SCI. Most Sip1 positive cells were oligodendrocytes. In vitro, Sip1 was weakly expressed in the cytoplasm of oligodendrocyte progenitor cells (OPCs), significantly up-regulated in immature oligodendrocytes, and showed significant nuclear transposition. In contrast, Sip1 expression levels in mature oligodendrocytes decreased to levels similar to those in OPCs. The RNA interference of Sip1 in OPCs reduced the level of myelin basic protein (a mature oligodendrocyte marker protein, MBP) and pERK1/2 (a key molecule of the ERK/MAPK pathway) in oligodendrocytes. These findings suggest that Sip1 is essential for oligodendrocyte differentiation and might affect the ERK/MAPK signal pathway. The results provide a theoretical basis for the treatment of demyelinating lesions such as spinal cord injury by regulating Sip1 expression in oligodendrocytes.

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

Transrectal electroejaculation combined with in-vitro fertilization: effective treatment of anejaculatory infertility due to spinal cord injury

Human Reproduction ◽

10.1093/humrep/12.12.2687 ◽

1997 ◽

Vol 12 (12) ◽

pp. 2687-2692 ◽

Cited By ~ 17

Author(s):

P. R. Brinsden ◽

S. M. Avery ◽

S. Marcus ◽

M. C. Macnamee

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

In Vitro Fertilization ◽

Effective Treatment ◽

Vitro Fertilization ◽

Cord Injury

Download Full-text

Immunosuppressants Affect Human Neural Stem Cells In Vitro but Not in an In Vivo Model of Spinal Cord Injury

Stem Cells Translational Medicine ◽

10.5966/sctm.2012-0175 ◽

2013 ◽

Vol 2 (10) ◽

pp. 731-744 ◽

Cited By ~ 21

Author(s):

Christopher J. Sontag ◽

Hal X. Nguyen ◽

Noriko Kamei ◽

Nobuko Uchida ◽

Aileen J. Anderson ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neural Stem Cells ◽

In Vivo Model ◽

Human Neural Stem Cells ◽

Cord Injury

Download Full-text

Depolarization and electrical stimulation enhance in vitro and in vivo sensory axon growth after spinal cord injury

Experimental Neurology ◽

10.1016/j.expneurol.2017.11.011 ◽

2018 ◽

Vol 300 ◽

pp. 247-258 ◽

Cited By ~ 12

Author(s):

Ioana Goganau ◽

Beatrice Sandner ◽

Norbert Weidner ◽

Karim Fouad ◽

Armin Blesch

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Electrical Stimulation ◽

Axon Growth ◽

Sensory Axon ◽

Cord Injury

Download Full-text

The role of exosomes derived from cerebrospinal fluid of spinal cord injury in neuron proliferation in vitro

Artificial Cells Nanomedicine and Biotechnology ◽

10.1080/21691401.2017.1304408 ◽

2017 ◽

Vol 46 (1) ◽

pp. 200-205 ◽

Cited By ~ 13

Author(s):

Fan-Long Kong ◽

Xiao-Ping Wang ◽

Ya-Nan Li ◽

Hai-Xu Wang

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cerebrospinal Fluid ◽

Cord Injury ◽

Proliferation In Vitro

Download Full-text

Small extracellular vesicles encapsulating CCL2 from activated astrocytes induce microglial activation and neuronal apoptosis after traumatic spinal cord injury

Journal of Neuroinflammation ◽

10.1186/s12974-021-02268-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Yuluo Rong ◽

Chengyue Ji ◽

Zhuanghui Wang ◽

Xuhui Ge ◽

Jiaxing Wang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Extracellular Vesicles ◽

Neuronal Apoptosis ◽

Microglial Activation ◽

Neuronal Cells ◽

Cell Communication ◽

Bioactive Lipids ◽

Cord Injury

Abstract Background Spinal cord injury (SCI) is a severe traumatic disease which causes high disability and mortality rates. The molecular pathological features after spinal cord injury mainly involve the inflammatory response, microglial and neuronal apoptosis, abnormal proliferation of astrocytes, and the formation of glial scars. However, the microenvironmental changes after spinal cord injury are complex, and the interactions between glial cells and nerve cells remain unclear. Small extracellular vesicles (sEVs) may play a key role in cell communication by transporting RNA, proteins, and bioactive lipids between cells. Few studies have examined the intercellular communication of astrocytes through sEVs after SCI. The inflammatory signal released from astrocytes is known to initiate microglial activation, but its effects on neurons after SCI remain to be further clarified. Methods Electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting were applied to characterize sEVs. We examined microglial activation and neuronal apoptosis mediated by astrocyte activation in an experimental model of acute spinal cord injury and in cell culture in vitro. Results Our results indicated that astrocytes activated after spinal cord injury release CCL2, act on microglia and neuronal cells through the sEV pathway, and promote neuronal apoptosis and microglial activation after binding the CCR2. Subsequently, the activated microglia release IL-1β, which acts on neuronal cells, thereby further aggravating their apoptosis. Conclusion This study elucidates that astrocytes interact with microglia and neurons through the sEV pathway after SCI, enriching the mechanism of CCL2 in neuroinflammation and spinal neurodegeneration, and providing a new theoretical basis of CCL2 as a therapeutic target for SCI.

Download Full-text

Cytokine and Growth Factor Activation In Vivo and In Vitro after Spinal Cord Injury

Mediators of Inflammation ◽

10.1155/2016/9476020 ◽

2016 ◽

Vol 2016 ◽

pp. 1-21 ◽

Cited By ~ 34

Author(s):

Elisa Garcia ◽

Jorge Aguilar-Cevallos ◽

Raul Silva-Garcia ◽

Antonio Ibarra

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Critical Role ◽

Glutamate Excitotoxicity ◽

Signaling Proteins ◽

Neurodegenerative Process ◽

Cord Injury ◽

Ion Imbalance

Spinal cord injury results in a life-disrupting series of deleterious interconnected mechanisms encompassed by the primary and secondary injury. These events are mediated by the upregulation of genes with roles in inflammation, transcription, and signaling proteins. In particular, cytokines and growth factors are signaling proteins that have important roles in the pathophysiology of SCI. The balance between the proinflammatory and anti-inflammatory effects of these molecules plays a critical role in the progression and outcome of the lesion. The excessive inflammatory Th1 and Th17 phenotypes observed after SCI tilt the scale towards a proinflammatory environment, which exacerbates the deleterious mechanisms present after the injury. These mechanisms include the disruption of the spinal cord blood barrier, edema and ion imbalance, in particular intracellular calcium and sodium concentrations, glutamate excitotoxicity, free radicals, and the inflammatory response contributing to the neurodegenerative process which is characterized by demyelination and apoptosis of neuronal tissue.

Download Full-text

Docosahexaenoic Acid-Loaded Polylactic Acid Core-Shell Nanofiber Membranes for Regenerative Medicine after Spinal Cord Injury: In Vitro and In Vivo Study

International Journal of Molecular Sciences ◽

10.3390/ijms21197031 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7031

Author(s):

Zhuo-Hao Liu ◽

Yin-Cheng Huang ◽

Chang-Yi Kuo ◽

Chao-Ying Kuo ◽

Chieh-Yu Chin ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Docosahexaenoic Acid ◽

Neurite Outgrowth ◽

Polylactic Acid ◽

In Vivo Study ◽

Core Shell ◽

Cord Injury

Spinal cord injury (SCI) is associated with disability and a drastic decrease in quality of life for affected individuals. Previous studies support the idea that docosahexaenoic acid (DHA)-based pharmacological approach is a promising therapeutic strategy for the management of acute SCI. We postulated that a nanostructured material for controlled delivery of DHA at the lesion site may be well suited for this purpose. Toward this end, we prepare drug-loaded fibrous mats made of core-shell nanofibers by electrospinning, which contained a polylactic acid (PLA) shell for encapsulation of DHA within the core, for delivery of DHA in situ. In vitro study confirmed sustained DHA release from PLA/DHA core-shell nanofiber membrane (CSNM) for up to 36 days, which could significantly increase neurite outgrowth from primary cortical neurons in 3 days. This is supported by the upregulation of brain-derived neurotropic factor (BDNF) and neurotrophin-3 (NT-3) neural marker genes from qRT-PCR analysis. Most importantly, the sustained release of DHA could significantly increase the neurite outgrowth length from cortical neuron cells in 7 days when co-cultured with PLA/DHA CSNM, compared with cells cultured with 3 μM DHA. From in vivo study with a SCI model created in rats, implantation of PLA/DHA CSNM could significantly improve neurological functions revealed by behavior assessment in comparison with the control (no treatment) and the PLA CSNM groups. According to histological analysis, PLA/DHA CSNM also effectively reduced neuron loss and increased serotonergic nerve sprouting. Taken together, the PLA/DHA CSNM may provide a nanostructured drug delivery system for DHA and contribute to neuroprotection and promoting neuroplasticity change following SCI.

Download Full-text