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Bone Marrow Mesenchymal Stem Cell Exosome Attenuates Inflammasome-Related Pyroptosis via Delivering circ_003564 to Improve the Recovery of Spinal Cord Injury

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Abstract

Bone marrow mesenchymal stem cell (BMSC) is previously reported to present a certain effect on treating spinal cord injury (SCI), while the underlying mechanism is largely uncovered. Therefore, the current study aimed to investigate the involvement of exosome-delivered circRNA profile in the BMSC’s effect on pyroptosis for SCI treatment. H2O2 treated rat primary neurons were cultured with normal medium, BMSC, BMSC plus GW4869, and BMSC-derived exosome, respectively, then inflammasome-related pyroptosis markers, and circRNA profiles were detected. Subsequently, circ_003564-knockdown BMSC exosome was transfected into H2O2 treated rat primary neurons and NGF-stimulated PC-12 cells. Furthermore, in vivo validation was conducted. BMSC and BMSC-derived exosome both decreased inflammasome-related pyroptosis markers including cleaved caspase-1, GSDMD, NLRP3, IL-1β, and IL-18 in H2O2-treated neurons, while exosome-free BMSC (BMSC plus GW4869) did not obviously reduce these factors. Microarray assay revealed that BMSC (vs. exosome-free BMSC) and BMSC-derived exosome (vs. normal medium) greatly regulated circRNA profiles, which were enriched in neuroinflammation pathways (such as neurotrophin, apoptosis, and TNF). Among three functional candidate circRNAs (circ_015525, circ_008876, and circ_003564), circ_003564 was most effective to regulate inflammasome-related pyroptosis. Interestingly, circ_003564-knockdown BMSC exosome showed higher expression of inflammasome-related pyroptosis markers compared to negative-control-knockdown BMSC exosome in H2O2 treated primary neurons/NGF-stimulated PC-12 cells. In vivo, BMSC exosome improved the function recovery and decreased tissue injury and inflammasome-related pyroptosis in SCI rats, whose effect was attenuated by circ_003564 knockdown transfection. BMSC exosome attenuates inflammasome-related pyroptosis via delivering circ_003564, contributing to its treatment efficacy for SCI.

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Availability of Data and Materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by National Natural Science Foundation of China (No. 81801209), Shanghai Clinical Medical Center (Grant Number 2017ZZ01023), and Shanghai Municipal Key Clinical Specialty (Grant Number shslczdzk00402, shslczdzk07001).

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  1. Yanyin Zhao and Yu Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

    Yanyin Zhao

  2. Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China

    Yu Chen

  3. Department of Orthopedics, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China

    Zhiwei Wang, Changli Xu, Tianze Liu, Ke Qi & Cheng Li

  4. Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China

    Suchi Qiao

  5. Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China

    Dake Tong

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  1. Yanyin Zhao
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Contributions

CL and DT contributed to the conception and design of the study. YZ and YC perform the experiments. ZW contributed to the data acquisition. CX and SQ contributed to the analysis and interpretation of data. TL drafted the manuscript. KQ contributed to revising of article. All authors read and approved the final manuscript.

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Correspondence to Dake Tong or Cheng Li.

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This study was approved by the Animal Care and Use Committee, and the experimental protocol was by the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

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Supplementary file1 (DOCX 21 KB)

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Supplementary file3

Supplementary figure 1. Isolation of BMSC and its exosome. BMSC marker expressions (A), BMSC morphology (B), size distribution of BMSC exosome (C), exosome marker expressions (D). (PNG 2873 kb)

High resolution image (TIF 4791 kb)

Supplementary file4

Supplementary figure 2. Inflammasome-related pyroptosis after H2O2 treatment. Protein expression of cleaved caspase 1, GSDMD, NLRP3, IL-1β, and IL-18 (A) between control and H2O2 groups. mRNA expression of GSDMD, NLRP3, IL-1β, and IL-18 (B) between control and H2O2 groups. (PNG 1281 kb)

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Supplementary file5

Supplementary figure 3. Circ_003564 expression after transfection. Circ_003564 expression in BMSC after transfection (A), circ_003564 expression in BMSC exosome after transfection (B). (PNG 337 kb)

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Zhao, Y., Chen, Y., Wang, Z. et al. Bone Marrow Mesenchymal Stem Cell Exosome Attenuates Inflammasome-Related Pyroptosis via Delivering circ_003564 to Improve the Recovery of Spinal Cord Injury. Mol Neurobiol 59, 6771–6789 (2022). https://doi.org/10.1007/s12035-022-03006-y

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