Cerebrospinal fluid-derived extracellular vesicles after spinal cord injury promote vascular regeneration via PI3K/AKT signaling pathway

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Abstract

Background

The cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, is predominantly produced by the choroid plexus of the ventricle. Although CSF-derived extracellular vesicles (CSF-EVs) may be utilized as diagnostic and prognostic indicators for illnesses of the central nervous system (CNS), it is uncertain if CSF-EVs may have an impact on neurological function after spinal cord injury (SCI).

Methods

Here, we isolated EVs using ultracentrifugation after extracting CSF from Bama miniature pigs. We then combined CSF-EVs with hydrogel and put it on the spinal cord's surface. To determine if CSF-EVs had an impact on mice's neurofunctional recovery, behavioral evaluations were employed. Both in vitro and in vivo, the effect of CSF-EVs on angiogenesis was assessed. We investigated whether CSF-EVs stimulated the PI3K/AKT pathway to alter angiogenesis using the PI3K inhibitor LY294002.

Results

CSF-EVs were successfully isolated and identified by transmission electron microscope (TEM), nano-tracking analysis (NTA), and western blot. CSF-EVs could be ingested by vascular endothelial cells as proved by in vivo imaging and immunofluorescence. We demonstrated that CSF-EVs derived from pigs with SCI (SCI-EVs) showed a better effect on promoting vascular regeneration as compared to CSF-EVs isolated from pigs receiving laminectomy (Sham-EVs). Behavioral assessments demonstrated that SCI-EVs could dramatically enhance motor and sensory function in mice with SCI. Western blot analysis suggested that SCI-EVs promote angiogenesis by activating PI3K/AKT signaling pathway, and the pro-angiogenetic effect of SCI-EVs was attenuated by the application of the LY294002 (PI3K inhibitor).

Conclusion

Our study revealed that CSF-EVs could enhance vascular regeneration by activating the PI3K/AKT pathway, hence improving motor function recovery after SCI, which may offer potential novel therapeutic options for acute SCI.

The translational potential of this article

This study demonstrated the promotion of vascular regeneration and neurological function of CSF-derived exosomes, which may provide a potential therapeutic approach for the treatment of spinal cord injury.

Graphical abstract

Abstract

The translational potential of this article: This study demonstrated the promotion of vascular regeneration and neurological function of CSF-derived exosomes, which may provide a potential therapeutic approach for the treatment of spinal cord injury.

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Most cited references 48

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Shedding light on the cell biology of extracellular vesicles

Guillaume van Niel, Gisela D'Angelo, Graça Raposo (2018)

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.

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Is Open Access

Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Valery L. Feigin, Emma Nichols, Tahiya Alam … (2020)

Summary Background Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders. Methods We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach. Findings Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247–308]) and second leading cause of deaths (9·0 million [8·8–9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34–44] and DALYs by 15% [9–21]) whereas their age-standardised rates decreased (deaths by 28% [26–30] and DALYs by 27% [24–31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6–46·1]), migraine (16·3% [11·7–20·8]), Alzheimer's and other dementias (10·4% [9·0–12·1]), and meningitis (7·9% [6·6–10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05–1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5–90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8–35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8–17·5] of DALYs are risk attributable). Interpretation Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies. Funding Bill & Melinda Gates Foundation.

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Traumatic spinal cord injury

Christopher Ahuja, Jefferson R Wilson, Satoshi Nori … (2017)

Traumatic spinal cord injury (SCI) has devastating consequences for the physical, social and vocational well-being of patients. The demographic of SCIs is shifting such that an increasing proportion of older individuals are being affected. Pathophysiologically, the initial mechanical trauma (the primary injury) permeabilizes neurons and glia and initiates a secondary injury cascade that leads to progressive cell death and spinal cord damage over the subsequent weeks. Over time, the lesion remodels and is composed of cystic cavitations and a glial scar, both of which potently inhibit regeneration. Several animal models and complementary behavioural tests of SCI have been developed to mimic this pathological process and form the basis for the development of preclinical and translational neuroprotective and neuroregenerative strategies. Diagnosis requires a thorough patient history, standardized neurological physical examination and radiographic imaging of the spinal cord. Following diagnosis, several interventions need to be rapidly applied, including haemodynamic monitoring in the intensive care unit, early surgical decompression, blood pressure augmentation and, potentially, the administration of methylprednisolone. Managing the complications of SCI, such as bowel and bladder dysfunction, the formation of pressure sores and infections, is key to address all facets of the patient's injury experience.

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Author and article information

Contributors

Yuxin Jin

Yong Cao

Chunyue Duan

Journal

Journal ID (nlm-ta): J Orthop Translat

Journal ID (iso-abbrev): J Orthop Translat

Title: Journal of Orthopaedic Translation

Publisher: Chinese Speaking Orthopaedic Society

ISSN (Print): 2214-031X

ISSN (Electronic): 2214-0328

Publication date PMC-release: 04 March 2023

Publication date Collection: March 2023

Publication date (Electronic): 04 March 2023

Volume: 39

Pages: 124-134

Affiliations

[a ]Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China

[b ]Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Xiangya Road 87, Changsha, 410008, China

[c ]National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China

Author notes

[∗ ]Corresponding author. Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China. docdcy@ 123456qq.com

[∗∗ ]Corresponding author. Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China. caoyong1912@ 123456163.com xycaoyong@ 123456csu.edu.cn

[∗∗∗ ]Corresponding author. Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China. 645391176@ 123456qq.com

Article

Publisher Item ID: S2214-031X(23)00011-6

DOI: 10.1016/j.jot.2023.02.001

PMC ID: 9999163

PubMed ID: 36909861

SO-VID: 123ecbe4-5a86-49a1-8bbb-1faa34248c1a

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 19 September 2022

Date revision received : 2 February 2023

Date accepted : 6 February 2023

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Cerebrospinal fluid-derived extracellular vesicles after spinal cord injury promote vascular regeneration via PI3K/AKT signaling pathway

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Abstract

Background

Methods

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Conclusion

The translational potential of this article

Graphical abstract

Abstract

Related collections

Bacterial extracellular vesicles

Most cited references 48

Shedding light on the cell biology of extracellular vesicles

Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Traumatic spinal cord injury

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Cited by 7

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