scholarly journals Enhancing Functional Recovery Through Intralesional Application of Extracellular Vesicles in a Rat Model of Traumatic Spinal Cord Injury

2022 ◽  
Vol 15 ◽  
Author(s):  
Pasquale Romanelli ◽  
Lara Bieler ◽  
Patrick Heimel ◽  
Siniša Škokić ◽  
Dominika Jakubecova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Extracellular Vesicles ◽  
Human Umbilical Cord ◽  
Traumatic Spinal Cord Injury ◽  
Early Application ◽  
Secondary Damage ◽  
Cord Injury ◽  
Inflammatory Processes ◽  
High Doses

Local inflammation plays a pivotal role in the process of secondary damage after spinal cord injury. We recently reported that acute intravenous application of extracellular vesicles (EVs) secreted by human umbilical cord mesenchymal stromal cells dampens the induction of inflammatory processes following traumatic spinal cord injury. However, systemic application of EVs is associated with delayed delivery to the site of injury and the necessity for high doses to reach therapeutic levels locally. To resolve these two constraints, we injected EVs directly at the lesion site acutely after spinal cord injury. We report here that intralesional application of EVs resulted in a more robust improvement of motor recovery, assessed with the BBB score and sub-score, as compared to the intravenous delivery. Moreover, the intralesional application was more potent in reducing inflammation and scarring after spinal cord injury than intravenous administration. Hence, the development of EV-based therapy for spinal cord injury should aim at an early application of vesicles close to the lesion.

scholarly journals Extracellular vesicles derived from CD73 modified human umbilical cord mesenchymal stem cells ameliorate inflammation after spinal cord injury

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiao Zhai ◽  
Kai Chen ◽  
Huan Yang ◽  
Bo Li ◽  
Tianjunke Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Human Umbilical Cord ◽  
M1 Polarization ◽  
Cord Injury

Abstract Background Spinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI. Methods CD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications. Results CD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1β, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4. Conclusions CD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy. Graphical Abstract

scholarly journals Human umbilical cord mesenchymal stem cells-derived extracellular vesicles facilitate the repair of spinal cord injury via the miR-29b-3p/PTEN/Akt/mTOR axis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiao Xiao ◽  
Weiwei Li ◽  
Dingchao Rong ◽  
Zhenchao Xu ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Motor Function ◽  
Extracellular Vesicles ◽  
Human Umbilical Cord ◽  
Permanent Disability ◽  
Cord Injury

AbstractSpinal cord injury (SCI) is a salient traumatic disease that often leads to permanent disability, and motor and sensory impairments. Human umbilical cord mesenchymal stem cells (HucMSCs) have a wide application prospect in the treatment of SCI. This study explored the repair effect of HucMSCs-derived extracellular vesicles (HucMSCs-EVs) on SCI. HucMSCs and HucMSCs-EVs were cultured and identified. The rat model of SCI was established, and SCI rats were treated with HucMSCs-EVs. The motor function of SCI rats and morphology of spinal cord tissues were evaluated. Levels of NeuN, GFAP, and NF200 in spinal cord tissues were detected and cell apoptosis was measured. SCI rats were treated with EVs extracted from miR-29b-3p inhibitor-transfected HucMSCs. The downstream gene and pathway of miR-29b-3p were examined. HucMSCs-EVs-treated rats showed obvious motor function recovery and reduced necrosis, nuclear pyknosis, and cavity. HucMSCs-EVs alleviated spinal cord neuronal injury. miR-29b-3p was poorly expressed in SCI tissues, but highly expressed in EVs and SCI rats treated with EVs. miR-29b-3p targeted PTEN. Inhibition of miR-29b-3p or overexpression of PTEN reversed the repair effect of EVs on SCI. EVs activated the AKT/mTOR pathway via the miR-29b-3p/PTEN. In conclusion, HucMSCs-EVs reduced pathological changes, improved motor function, and promoted nerve function repair in SCI rats via the miR-29b-3p/PTEN/Akt/mTOR axis.

Role of Acid-Sensing Ion Channel 1a in the Secondary Damage of Traumatic Spinal Cord Injury

2011 ◽  
Vol 254 (2) ◽  
pp. 353-362 ◽  
Author(s):  
Rong Hu ◽  
Bo Duan ◽  
Dianshi Wang ◽  
Ye Yu ◽  
Weiguang Li ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Ion Channel ◽  
Traumatic Spinal Cord Injury ◽  
Secondary Damage ◽  
Cord Injury

scholarly journals Management of Acute Traumatic Spinal Cord Injury: A Review of the Literature

2021 ◽  
Vol 8 ◽  
Author(s):  
Timothy Y. Wang ◽  
Christine Park ◽  
Hanci Zhang ◽  
Shervin Rahimpour ◽  
Kelly R. Murphy ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Spinal Injury ◽  
Optimal Recovery ◽  
Neurological Dysfunction ◽  
Traumatic Spinal Cord Injury ◽  
Term Care ◽  
Secondary Damage ◽  
Severity Of Injury ◽  
Cord Injury

Traumatic spinal cord injury (TSCI) is a debilitating disease that poses significant functional and economic burden on both the individual and societal levels. Prognosis is dependent on the extent of the spinal injury and the severity of neurological dysfunction. If not treated rapidly, patients with TSCI can suffer further secondary damage and experience escalating disability and complications. It is important to quickly assess the patient to identify the location and severity of injury to make a decision to pursue a surgical and/or conservative management. However, there are many conditions that factor into the management of TSCI patients, ranging from the initial presentation of the patient to long-term care for optimal recovery. Here, we provide a comprehensive review of the etiologies of spinal cord injury and the complications that may arise, and present an algorithm to aid in the management of TSCI.

scholarly journals Engineered extracellular vesicles derived from primary M2 macrophages with anti-inflammatory and neuroprotective properties for the treatment of spinal cord injury

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chuanjie Zhang ◽  
Daoyong Li ◽  
Hengshuo Hu ◽  
Zhe Wang ◽  
Jinyu An ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Nerve Cell ◽  
Extracellular Vesicles ◽  
Cell Damage ◽  
Neuroprotective Effect ◽  
M2 Macrophages ◽  
Secondary Damage ◽  
Cord Injury ◽  
Anti Inflammatory

Abstract Background Uncontrollable inflammation and nerve cell apoptosis are the most destructive pathological response after spinal cord injury (SCI). So, inflammation suppression combined with neuroprotection is one of the most promising strategies to treat SCI. Engineered extracellular vesicles with anti-inflammatory and neuroprotective properties are promising candidates for implementing these strategies for the treatment of SCI. Results By combining nerve growth factor (NGF) and curcumin (Cur), we prepared stable engineered extracellular vesicles of approximately 120 nm from primary M2 macrophages with anti-inflammatory and neuroprotective properties (Cur@EVs−cl−NGF). Notably, NGF was coupled with EVs by matrix metalloproteinase 9 (MMP9)-a cleavable linker to release at the injured site accurately. Through targeted experiments, we found that these extracellular vesicles could actively and effectively accumulate at the injured site of SCI mice, which greatly improved the bioavailability of the drugs. Subsequently, Cur@EVs−cl−NGF reached the injured site and could effectively inhibit the uncontrollable inflammatory response to protect the spinal cord from secondary damage; in addition, Cur@EVs−cl−NGF could release NGF into the microenvironment in time to exert a neuroprotective effect against nerve cell damage. Conclusions A series of in vivo and in vitro experiments showed that the engineered extracellular vesicles significantly improved the microenvironment after injury and promoted the recovery of motor function after SCI. We provide a new method for inflammation suppression combined with neuroprotective strategies to treat SCI. Graphical Abstract

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