Microglia-Derived Exosomal microRNA-151-3p Enhances Functional Healing After Spinal Cord Injury by Attenuating Neuronal Apoptosis <i>via</i> Regulating the p53/p21/CDK1 Signaling Pathway

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Abstract

Spinal cord injury (SCI) is a catastrophic event mainly involving neuronal apoptosis and axonal disruption, and it causes severe motor and sensory deficits. Due to the complicated pathological process of SCI, there is currently still a lack of effective treatment for SCI. Microglia, a type of immune cell residing in the central nervous system (CNS), need to respond to various stimuli to protect neuronal cells from death. It was also reported that microRNAs (miRNAs) had been identified in microglia-derived exosomes that can be taken up by neurons. However, the kinds of miRNAs in exosome cargo derived from microglia and the underlying mechanisms by which they contribute to neuroprotection after SCI remain unknown. In the present study, a contusive SCI mouse model and in vitro experiments were applied to explore the therapeutic effects of microglia-derived exosomes on neuronal apoptosis, axonal regrowth, and functional recovery after SCI. Then, miRNA analysis, rescue experiments, and luciferase activity assays for target genes were performed to confirm the role and underlying mechanism of microglia-derived exosomal miRNAs in SCI. We revealed that microglia-derived exosomes could promote neurological functional recovery by suppressing neuronal apoptosis and promoting axonal regrowth both in vivo and in vitro. MicroRNA-151-3p is abundant in microglia-derived exosomes and is necessary for mediating the neuroprotective effect of microglia-derived exosomes for SCI repair. Luciferase activity assays reported that P53 was the target gene for miR-151-3p and that p53/p21/CDK1 signaling cascades may be involved in the modulation of neuronal apoptosis and axonal regrowth by microglia-derived exosomal microRNA-151-3p. In conclusion, our data demonstrated that microglia-derived exosomes (microglia-Exos) might be a promising, cell-free approach for the treatment of SCI. MicroRNA-151-3p is the key molecule in microglia-derived exosomes that mediates the neuroprotective effects of SCI treatments.

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ATP mediates rapid microglial response to local brain injury in vivo.

Dimitrios Davalos, Jaime Grutzendler, Guang. Yang … (2005)

Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.

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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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Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage.

Ansar Karimian, Seyyed Amir Yasin Ahmadi, Bahman Yousefi (2016)

An appropriate control over cell cycle progression depends on many factors. Cyclin-dependent kinase (CDK) inhibitor p21 (also known as p21(WAF1/Cip1)) is one of these factors that promote cell cycle arrest in response to a variety of stimuli. The inhibitory effect of P21 on cell cycle progression correlates with its nuclear localization. P21 can be induced by both p53-dependent and p53-independent mechanisms. Some other important functions attributed to p21 include transcriptional regulation, modulation or inhibition of apoptosis. These functions are largely dependent on direct p21/protein interactions and also on p21 subcellular localizations. In addition, p21 can play a role in DNA repair by interacting with proliferating cell nuclear antigen (PCNA). In this review, we will focus on the multiple functions of p21 in cell cycle regulation, apoptosis and gene transcription after DNA damage and briefly discuss the pathways and factors that have critical roles in p21 expression and activity.

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Author and article information

Contributors

Chengjun Li: URI : https://loop.frontiersin.org/people/1343828/overview

Tian Qin: URI : https://loop.frontiersin.org/people/1480400/overview

Hongbin Lu: URI : https://loop.frontiersin.org/people/611197/overview

Yong Cao: URI : https://loop.frontiersin.org/people/954642/overview

Journal

Journal ID (nlm-ta): Front Cell Dev Biol

Journal ID (iso-abbrev): Front Cell Dev Biol

Journal ID (publisher-id): Front. Cell Dev. Biol.

Title: Frontiers in Cell and Developmental Biology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2296-634X

Publication date (Electronic): 20 January 2022

Publication date Collection: 2021

Volume: 9

Electronic Location Identifier: 783017

Affiliations

[1] ¹ Department of Spine Surgery and Orthopaedics , Xiangya Hospital , Central South University , Changsha, China

[2] ² National Clinical Research Center for Geriatric Disorders , Xiangya Hospital , Central South University , Changsha, China

[3] ³ Key Laboratory of Organ Injury , Aging and Regenerative Medicine of Hunan Province , Changsha, China

[4] ⁴ Department of Sports Medicine , Research Centre of Sports Medicine , Xiangya Hospital , Central South University , Changsha, China

Author notes

Edited by: Kailiang Zhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, China

Reviewed by: Houqing Long, The First Affiliated Hospital of Sun Yat-sen University, China

Masaki Ueno, Niigata University, Japan

*Correspondence: Chunyue Duan, docdcy@ 123456qq.com ; Yong Cao, caoyong1912@ 123456163.com ; Jianzhong Hu, jianzhonghu@ 123456hotmail.com

[ † ]

These authors have contributed equally to this work

This article was submitted to Cell Death and Survival, a section of the journal Frontiers in Cell and Developmental Biology

Article

Publisher ID: 783017

DOI: 10.3389/fcell.2021.783017

PMC ID: 8811263

PubMed ID: 35127706

SO-VID: 0fc6d7ea-8f96-4ec9-b064-79d05ba02172

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 25 September 2021

Date accepted : 27 December 2021

Funding

Funded by: Fundamental Research Funds for Central Universities of the Central South University , doi 10.13039/501100012476;

Award ID: 2020zzts270

Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;

Funded by: Natural Science Foundation of Hunan Province , doi 10.13039/501100004735;

Microglia-Derived Exosomal microRNA-151-3p Enhances Functional Healing After Spinal Cord Injury by Attenuating Neuronal Apoptosis via Regulating the p53/p21/CDK1 Signaling Pathway

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Abstract

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Neuronal Signaling

Most cited references 43

ATP mediates rapid microglial response to local brain injury in vivo.

Traumatic spinal cord injury

Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage.

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