EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats

AbstractBackgroundSpinal cord injury (SCI) causes devastating loss of function and neuronal death without effective treatment. (−)-Epigallocatechin-3-gallate (EGCG) has antioxidant properties and plays an essential role in the nervous system. However, the underlying mechanism by which EGCG promotes neuronal survival and functional recovery in complete spinal cord transection (ST) remains unclear.MethodsIn the present study, we established primary cerebellar granule neurons (CGNs) and a T10 ST rat model to investigate the antioxidant effects of EGCG via its modulation of protein kinase D1 (PKD1) phosphorylation and inhibition of ferroptosis.ResultsWe revealed that EGCG significantly increased the cell survival rate of CGNs and PKD1 phosphorylation levels in comparison to the vehicle control, with a maximal effect observed at 50 µM. EGCG upregulated PKD1 phosphorylation levels and inhibited ferroptosis to reduce the cell death of CGNs under oxidative stress and to promote functional recovery and ERK phosphorylation in rats following complete ST.ConclusionTogether, these results lay the foundation for EGCG as a novel strategy for the treatment of SCI related to PKD1 phosphorylation and ferroptosis.

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Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis

10.21203/rs.3.rs-38209/v2 ◽

2020 ◽

Author(s):

Yong Cao ◽

Xu Yan ◽

Chunyuan Chen ◽

Hui Xie ◽

Hongbin Lu ◽

...

Keyword(s):

Spinal Cord ◽

Signaling Pathway ◽

Functional Recovery ◽

Underlying Mechanism ◽

Akt Signaling ◽

Tube Formation ◽

Akt Signaling Pathway ◽

Functional Studies ◽

Cord Injury

Abstract Background: Spinal cord injury is a devastating clinical condition for which there are currently no effective therapeutic options. In the present study, we aim to investigate the effect of an administered injection of exosomes derived human urine stem cell (USC-Exo) embedded in hydrogel could improve the spinal cord functional recovery after injury and the underlying mechanism.Methods: Exosome were isolate from USC and identified by transmission electron Microscopy (TEM) and western blot. Functional assays in vitro were performed to assess the effects of USC-Exo on tube formation and migration, as well as their regulatory role in the PI3K/AKT signaling pathway activation. A locally administered injection of exosome embedded in hydrogel was used for SCI treatment. The effects of USC-Exo on functional recovery and the role of the candidate protein ANGPTL3 harboring in USC-Exo for promoting angiogenesis in SCI model was assessed.Results: In the current study, we demonstrate that a locally administered injection of USC-Exo embedded in hydrogel can pass the spinal cord blood brain barrier and deliver ANGPTL3 to the injured spinal cord region. In addition, the administration of human USC-Exo could enhance spinal cord neurological functional recovery by promoting angiogenesis. The results of mechanistic studies revealed that ANGPTL3 is enriched in (USC-Exo) and is required for their ability to promote angiogenesis. Functional studies further confirmed that the effects of USC-Exo on angiogenesis are mediated by the PI3K/AKT signaling pathway. Conclusion: Collectively, our results indicate that USC-Exo serve as a crucial regulator of angiogenesis by delivering ANGPTL3 and may represent a promising novel therapeutic agent for SCI repair.

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PTEN Blocking Stimulates Corticospinal and Raphespinal Axonal Regeneration and Promotes Functional Recovery After Spinal Cord Injury

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa147 ◽

2020 ◽

Author(s):

Saurav Bhowmick ◽

P M Abdul-Muneer

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Growth Failure ◽

Axon Growth ◽

Underlying Mechanism ◽

Intrinsic Factors ◽

Tensin Homolog ◽

Cord Injury ◽

Novel Strategy ◽

Antagonistic Peptide

Abstract The long-term disabilities associated with spinal cord injury (SCI) are primarily due to the absence of robust neuronal regeneration and functional plasticity. The inability of the axon to regenerate after SCI is contributed by several intrinsic factors that trigger a cascade of molecular growth program and modulates axonal sprouting. Phosphatase and tensin homolog (PTEN) is one of the intrinsic factors contributing to growth failure after SCI, however, the underlying mechanism is not well known. Here, we developed a novel therapeutic approach for treating SCI by suppressing the action of PTEN in a mouse model of hemisection SCI. We have used a novel peptide, PTEN antagonistic peptide (PAP) to block the critical domains of PTEN to demonstrate its ability to potentially promote axon growth. PAP treatment not only enhanced regeneration of corticospinal axons into the caudal spinal cord but also promoted the regrowth of descending serotonergic axons in SCI mice. Furthermore, expression levels of p-mTOR, p-S6, p-Akt, p-Erk, p-GSK, p-PI3K downstream of PTEN signaling pathway were increased significantly in the spinal cord of SCI mice systemically treated with PAP than control TAT peptide-treated mice. Our novel strategy of administering deliverable compounds postinjury may facilitate translational feasibility for central nervous system injury.

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Neural stem cell-derived exosomes facilitate spinal cord functional recovery after injury by promoting angiogenesis

Experimental Biology and Medicine ◽

10.1177/1535370219895491 ◽

2020 ◽

Vol 245 (1) ◽

pp. 54-65 ◽

Cited By ~ 6

Author(s):

Dong Zhong ◽

Yong Cao ◽

Cheng-Jun Li ◽

Miao Li ◽

Zi-Jie Rong ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Underlying Mechanism ◽

Regeneration Ability ◽

Therapeutic Effects ◽

Cord Injury ◽

Angiogenic Effect

Acute traumatic spinal cord injury is a devastating event without effective therapeutic approach. The feeble plasticity of spinal cord microvascular endothelial cells (SCMECs) after trauma is one of the major causes for the exacerbation of spinal cord injury. Therefore, improving the plasticity and regeneration of SCMECs is crucial to promote recovery after spinal cord injury. For the present study, we explored the influence of exosomes derived from neural stem cells (NSCs-Exos) on the spinal cord microvascular regeneration after spinal cord injury and determined the underlying mechanisms. After the primary NSCs and SCMECs were extracted, exosomes were isolated from NSCs conditioned medium and used to co-incubated with the SCMECs in vitro, and then the effect of exosomes on the angiogenic activities of SCMECs was measured. The candidate molecules involved in the NSCs-Exos-mediated angiogenesis were screened using Western blotting. The effect of NSCs-Exos on angiogenesis and spinal cord functional recovery after injury in vivo was analyzed. The results demonstrated that NSCs-Exos could enhance the angiogenic activities of SCMECs, and were highly enriched in VEGF-A. The level of VEGF-A was downregulated in NSCsshVEGF-A-Exos and the pro-angiogenic effects on cocultured SCMECs were inhibited. Furthermore, NSCs-Exos significantly accelerated the microvascular regeneration, reduced the spinal cord cavity, and improved the Basso mouse scale scores in spinal cord injury mice. This work provides the evidence of the underlying mechanism of NSCs-Exos-mediated angiogenesis and suggests a novel therapeutic target for spinal cord injury. Impact statement The feeble plasticity of SCMECs after trauma is one of the major causes for the exacerbation of SCI. Therefore, improving the regeneration ability of SCMECs is crucial to promote spinal cord functional recovery after injury. Our current study uncovered that NSCs-Exos could promote SCMECs migration, tube formation and proliferation in vitro, and further identified that exosomal VEGF-A mediated the pro-angiogenic effect. Furthermore, we observed a remarkable microvascular density increase, spinal cord cavity shrinkage, and motor function recovery in SCI mice treated with NSCs-Exos, which confirmed the therapeutic effects of NSCs-Exos to alleviate SCI. Downregulating VEGF-A partially abolished these effects of NSCs-Exos. This is the first study to reveal that NSCs-Exos has the pro-angiogenic effect on SCMECs by transferring VEGF-A and promote microvascular regeneration and tissue healing, indicating that NSCs-Exos can become a promising therapeutic bioagent for facilitating the functional recovery of SCI.

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Deletion or inhibition of astrocytic transglutaminase 2 promotes functional recovery after spinal cord injury

10.1101/2021.09.15.460455 ◽

2021 ◽

Author(s):

Anissa Elahi ◽

Jacen Emerson ◽

Jacob Rudlong ◽

Jeffrey W. Keillor ◽

Garrick Salois ◽

...

Keyword(s):

Spinal Cord ◽

Functional Recovery ◽

Molecular Mechanisms ◽

Genetic Model ◽

Transglutaminase 2 ◽

Cns Injury ◽

Metabolic Coupling ◽

Cord Injury ◽

Spinal Cord Contusion ◽

Novel Strategy

AbstractFollowing CNS injury astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/-TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO_mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days postinjury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis reveals a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron-astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.

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Ferrostatin-1 Alleviates White Matter Injury via Decreasing Ferroptosis Following Spinal Cord Injury

10.21203/rs.3.rs-405886/v1 ◽

2021 ◽

Author(s):

Hongfei Ge ◽

Xingsen Xue ◽

Jishu Xian ◽

Linbo Yuan ◽

Long Wang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

White Matter ◽

Functional Recovery ◽

Underlying Mechanism ◽

Neurological Impairment ◽

White Matter Injury ◽

Oligodendrocyte Progenitor Cells ◽

White Matter Damage ◽

Cord Injury

Abstract Spinal cord injury (SCI), a devastating neurological impairment, ubiquitously imposes a long-term psychological stress and high socioeconomic burden for the suffers and their family. To date, recent researchers have paid arousing attention to white matter injury and uncovering the underlying mechanism post-SCI. Ferroptosis, to our knowledge, has been revealed to be associated with diverse diseases including stroke, cancer, and kidney degeneration. However, its role in white matter damage after SCI remains unclear. Ferrostatin-1, a potent inhibitor of ferroptosis, has been illustrated to curb ferroptosis in neurons, subsequently improve functional recovery after traumatic brain injury (TBI). But whether it inhibits white matter injury post-SCI is still unknown. Here, our results indicated that ferroptosis played an important role in the secondary white matter injury following SCI and ferrostatin-1 could reduce iron and reactive oxygen species (ROS) accumulation, downregulate the ferroptosis-related genes and its products of IREB2 and PTGS2 to further inhibit ferroptosis in oligodendrocyte progenitor cells (OPCs), finally reducing white matter injury and promoting functional recovery following SCI in rats, which enlarges the therapeutic scope for ferrostatin-1 and deciphers the potential mechanism of white matter damage after SCI.

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Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02078-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yong Cao ◽

Yan Xu ◽

Chunyuan Chen ◽

Hui Xie ◽

Hongbin Lu ◽

...

Keyword(s):

Spinal Cord ◽

Signaling Pathway ◽

Functional Recovery ◽

Underlying Mechanism ◽

Akt Signaling ◽

Tube Formation ◽

Akt Signaling Pathway ◽

Functional Studies ◽

Cord Injury

Abstract Background Spinal cord injury is a devastating clinical condition for which there are currently no effective therapeutic options. In the present study, we aim to investigate if the effect of an administered injection of exosomes derived from human urine stem cell (USC-Exo) embedded in hydrogel could improve the spinal cord functional recovery after injury and the underlying mechanism. Methods Exosomes were isolated from USC and identified by transmission electron microscopy (TEM) and Western blot. Functional assays in vitro were performed to assess the effects of USC-Exo on tube formation and migration, as well as their regulatory role in the PI3K/AKT signaling pathway activation. A locally administered injection of exosome embedded in hydrogel was used for SCI treatment. The effects of USC-Exo on functional recovery and the role of the candidate protein ANGPTL3 harboring in USC-Exo for promoting angiogenesis in SCI model were assessed. Results In the current study, we demonstrate that a locally administered injection of USC-Exo embedded in hydrogel can pass the spinal cord blood-brain barrier and deliver ANGPTL3 to the injured spinal cord region. In addition, the administration of human USC-Exo could enhance spinal cord neurological functional recovery by promoting angiogenesis. The results of mechanistic studies revealed that ANGPTL3 is enriched in USC-Exo and is required for their ability to promote angiogenesis. Functional studies further confirmed that the effects of USC-Exo on angiogenesis are mediated by the PI3K/AKT signaling pathway. Conclusion Collectively, our results indicate that USC-Exo serve as a crucial regulator of angiogenesis by delivering ANGPTL3 and may represent a promising novel therapeutic agent for SCI repair.

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Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2010.mayjun01 ◽

2010 ◽

Vol 15 (3) ◽

pp. 1-7

Author(s):

Richard T. Katz

Keyword(s):

Spinal Cord ◽

Spinal Cord Injuries ◽

Functional Independence ◽

Outcome Data ◽

Multiple Organ ◽

Loss Of Function ◽

Sixth Edition ◽

Organ Systems ◽

Cord Injury ◽

Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

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