A mouse model of complete-crush transection spinal cord injury made by two operations

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Abstract

Background

More and more studies have focused on the treatment of spinal cord injury (SCI) by tissue engineering, but there is still no ideal animal model that can genuinely and objectively simulate the real pathological process in clinical practice. Also, given the increasing availability and use of genetically modified animals in basic science research, it has become essential to develop clinically related models for SCI for use in mice.

Methods

Forty-eight C57BL/6 mice were divided into three groups (injured/sham/uninjured). We determined the scar range made by the first crush injury by specimen observation, hematoxylin and eosin (HE) staining, and immunofluorescence staining. Transection to completely remove a 2-mm spinal cord segment centered on the lesion core was completed 6 weeks after the first injury in injured groups, whereas the sham group only underwent re-exposure of the spinal cord without transection injury. The characteristics of this SCI model were fully ascertained by specimen observation, HE staining, immunofluorescence staining, and quantitative real-time polymerase chain reaction (qRT-PCR).

Results

No mice died after the first injury. Histopathological findings suggested a scar range of 2 mm. After the second operation, 2 mice of the injured group and 1 mouse of the sham group died. The Basso Mouse Scale (BMS) score and motor evoked potential (MEP) results showed that the neurological function of mice did not recover. Immunostaining showed that there were no neurons or neurofilament residues in the lesion core 4 weeks after the second injury. Astrocytes encapsulated immune cells to form dense glial scars. Most immune cells were confined to the core of the lesion and formed fibrous scars with the fibroblasts. At the same time, there was considerable angiogenesis in the lesion core and around the injury. The results of qRT-PCR showed that Ptprc was highly expressed in the lesion core, while Gfap, nestin, Cnp, and Sv2b were highly expressed in the adjacent region. This suggests that the lesion core is a highly inflammatory zone, but there may be spontaneous neurogenesis adjacent to the lesion core.

Conclusions

The mouse crash-complete transection SCI model made by the two operations has good simulation, high feasibility, and high reproducibility; it will be a useful tool for pre-clinical testing of SCI treatment.

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Most cited references 51

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Astrocyte scar formation aids central nervous system axon regeneration.

Mark A Anderson, Joshua Burda, Yilong Ren … (2016)

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.

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Molecular dissection of reactive astrogliosis and glial scar formation.

Michael Sofroniew (2009)

Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Reactive astrocytes can have both loss of normal functions and gain of abnormal effects that could feature prominently in a variety of disease processes. This article reviews developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis and highlights the potential to identify novel therapeutic molecular targets for diverse neurological disorders.

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Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury.

Ina B Wanner, Mark A Anderson, Bingbing Song … (2013)

Astroglial scars surround damaged tissue after trauma, stroke, infection, or autoimmune inflammation in the CNS. They are essential for wound repair, but also interfere with axonal regrowth. A better understanding of the cellular mechanisms, regulation, and functions of astroglial scar formation is fundamental to developing safe interventions for many CNS disorders. We used wild-type and transgenic mice to quantify and dissect these parameters. Adjacent to crush spinal cord injury (SCI), reactive astrocytes exhibited heterogeneous phenotypes as regards proliferation, morphology, and chemistry, which all varied with distance from lesions. Mature scar borders at 14 d after SCI consisted primarily of newly proliferated astroglia with elongated cell processes that surrounded large and small clusters of inflammatory, fibrotic, and other cells. During scar formation from 5 to 14 d after SCI, cell processes deriving from different astroglia associated into overlapping bundles that quantifiably reoriented and organized into dense mesh-like arrangements. Selective deletion of STAT3 from astroglia quantifiably disrupted the organization of elongated astroglia into scar borders, and caused a failure of astroglia to surround inflammatory cells, resulting in increased spread of these cells and neuronal loss. In cocultures, wild-type astroglia spontaneously corralled inflammatory or fibromeningeal cells into segregated clusters, whereas STAT3-deficient astroglia failed to do so. These findings demonstrate heterogeneity of reactive astroglia and show that scar borders are formed by newly proliferated, elongated astroglia, which organize via STAT3-dependent mechanisms to corral inflammatory and fibrotic cells into discrete areas separated from adjacent tissue that contains viable neurons.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Transl Med

Journal ID (iso-abbrev): Ann Transl Med

Journal ID (publisher-id): ATM

Title: Annals of Translational Medicine

Publisher: AME Publishing Company

ISSN (Print): 2305-5839

ISSN (Electronic): 2305-5847

Publication date (Print and electronic): March 2020

Publication date (Print): March 2020

Volume: 8

Issue: 5

Electronic Location Identifier: 210

Affiliations

[1 ]Division of Spine Surgery, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine , Shanghai 200065, China;

[2 ]Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration, Tongji University, Ministry of Education , Shanghai 200065, China;

[3 ]Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA, USA

Author notes

Contributions: (I) Conception and design: C Li, Z Wu, L Cheng; (II) Administrative support: L Cheng; (III) Provision of study materials or patients: C Li, Z Wu; (IV) Collection and assembly of data: CM Lee, X Zhu; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

[#]

These authors contributed equally to this work.

Correspondence to: Liming Cheng. Division of Spine Surgery, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Email: limingcheng@ 123456tongji.edu.cn .

Article

Publisher ID: atm-08-05-210

DOI: 10.21037/atm.2020.01.58

PMC ID: 7154420

PubMed ID: 32309357

SO-VID: 6b117525-8b7b-476d-b59f-6011c56c8c01

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

History

Date received : 09 September 2019

Date accepted : 02 January 2020

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A mouse model of complete-crush transection spinal cord injury made by two operations

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Abstract

Background

Methods

Results

Conclusions

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Animal models of intrauterine growth restriction (IUGR)

Most cited references 51

Astrocyte scar formation aids central nervous system axon regeneration.

Molecular dissection of reactive astrogliosis and glial scar formation.

Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury.

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