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Amelioration of White Matter Injury Through Mitigating Ferroptosis Following Hepcidin Treatment After Spinal Cord Injury

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Abstract

Spinal cord injury (SCI) usually introduces permanent or long-lasting neurological impairments. Maintaining the integrity of the limited number of white matter bundles (5–10%) preserves wholly or partially locomotor following SCI. Considering that the basic structure of white matter bundles is axon wrapped by oligodendrocytes, promoting oligodendrocytes survival might be a feasible strategy for reducing white matter injury (WMI) after SCI. Oligodendrocytes are rich in unsaturated fatty acid and susceptible to ferroptosis-induced damage. Hence, exploring method to reduce ferroptosis is supposed to expedite oligodendrocytes survival, thereafter mitigating WMI to facilitate functional recovery post-SCI. Here, the results indicated the administration of hepcidin reduced iron accumulation to promote oligodendrocytes survival and to decrease spinal cord atrophy, therefore facilitating functional recovery. Then, the WMI was evidently decreased owing to attenuating ferroptosis. Subsequently, the results revealed that the expression of divalent metal transporter 1 (DMT1) and transferrin receptor (TfR) was expressed in CC1+ cells. The expression level of DMT1 and TfR was significantly increased, while this phenomenon was obviously neutralized with the administration of hepcidin in the epicenter of spinal cord after SCI. Afterward, the application of hepcidin downregulated reactive oxygen species (ROS) overload, which was evidently increased with the treatment of 20 μM FeCl3, therefore increasing cell viability and reducing lactate dehydrogenase (LDH) activity through downregulating the expression of DMT1 and TfR to inhibit ferroptosis in oligodendrocyte progenitor cells (OPCs). The present study provides evidence that the application of hepcidin facilitates oligodendrocytes survival to alleviate WMI via reducing the expression of DMT1 and TfR.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

SCI:

Spinal cord injury

WMI:

White matter injury

DMT1:

Divalent metal transporter 1

TfR:

Transferrin receptor

ROS:

Reactive oxygen species

LDH:

Lactate dehydrogenase

OPCs:

Oligodendrocyte progenitor cells

GPER1:

G-protein coupled estrogen receptor 1

NSC:

Neural stem cell

MSC:

Mesenchymal stem cell

Fpn1:

Ferroportin 1

PBS:

Phosphate-buffered saline

DMEM:

Dulbecco’s modified Eagle’s medium

bFGF:

Basic fibroblast growth factor

PDGF:

Platelet-derived growth factor

HE:

Hematoxylin and eosin

IHC:

Immunohistochemistry

DAB:

3-Diaminobenzidine

TEM:

Transmission electron microscopy

BCA:

Bicinchoninic acid

PVDF:

Polyvinylidene difluoride

CCK8:

Cell counting kit-8

dMBP:

Degraded myelin basic protein

APP:

Amyloid precursor protein

AD:

Alzheimer’s disease

HRP:

Horseradish peroxidase

RT-qPCR:

Reverse transcription-quantitative polymerase chain reaction

FSP1:

Ferroptosis suppressor protein 1 (FSP1)

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Funding

This work was supported by grants from the National Natural Science Foundation of China (approval no. 81471261) and Natural Science Foundation of Chongqing (approval no. cstc2018jcyjAX0080).

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Author notes

  1. Jiantao Shi, Xingsen Xue and Linbo Yuan contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, People’s Republic of China

    Jiantao Shi, Xingsen Xue, Linbo Yuan, Guangjian He, Zhouyang Jiang, Long Wang, Jiali Zhang, Hong Su, Jishu Xian, Chuhua Fu & Shengli Hu

  2. Department of Neurosurgery, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, 441011, Xiangyang, Hubei, People’s Republic of China

    Chuhua Fu

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  1. Jiantao Shi
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Contributions

Jiantao Shi, Xingsen Xue, and Linbo Yuan performed most of the experiments, with assistance from Guanjian He, Zhouyang Jiang, Long Wang, Jiali Zhang, and Hong Su. Zhouyang Jiang and Long Wang analyzed the results and edited figures. Jiantao Shi, Xingsen Xue, and Linbo Yuan performed SCI model and statistical analysis. Guanjian He and Jiali Zhang performed cell culture and treatments. Jiantao Shi, Xingsen Xue, and Jishu Xian performed immunoblotting and immunostaining. Jiantao Shi wrote preliminary draft of the manuscript. Chuhua Fu designed experiments and revised the manuscript. Shengli Hu made the hypothesis and revised the manuscript. All authors approved final version of the manuscript.

Corresponding authors

Correspondence to Chuhua Fu or Shengli Hu.

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Research Involving Animals

The animal experiment procedures were implemented according to the China’s animal welfare legislation for the protection of animals used for scientific purposes. And, this work was supervised by the Ethics Committee of the Southwest Hospital, Third Military Medical University (Army Medical University) for the use of laboratory animals (approval no. AMUWEC20210017).

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Shi, J., Xue, X., Yuan, L. et al. Amelioration of White Matter Injury Through Mitigating Ferroptosis Following Hepcidin Treatment After Spinal Cord Injury. Mol Neurobiol 60, 3365–3378 (2023). https://doi.org/10.1007/s12035-023-03287-x

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