Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Orthop. Feb 18, 2023; 14(2): 64-82
Published online Feb 18, 2023. doi: 10.5312/wjo.v14.i2.64
Mechanism of spinal cord injury regeneration and the effect of human neural stem cells-secretome treatment in rat model
I Nyoman Semita, Dwikora Novembri Utomo, Heri Suroto
I Nyoman Semita, Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia
I Nyoman Semita, Department of Orthopedic and Traumatology, Faculty of Medicine, University of Jember, Jember 68121, Indonesia
Dwikora Novembri Utomo, Heri Suroto, Department of Orthopedic and Traumatology, Faculty of Medicine, Universitas Airlangga, Surabaya 60118, East Java, Indonesia
Author contributions: Semita IN, Utomo DN, and Suroto H designed and coordinated the study; Semita IN performed the experiments, acquired and analyzed data; Semita IN interpreted the data; Semita IN wrote the manuscript; and all authors approved the final version of the article.
Institutional animal care and use committee statement: All experimental procedures were carefully reviewed and approved Biomedical Veterinary Laboratory, Faculty of Dentistry, University of Jember, Surabaya, Indonesia (REC.1462/UN25.8/KEPK/DL/2021). All rats were approved by Department of Food and Livestock Health (No.503/A.1/0005. B/35.09.325/2020).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dwikora Novembri Utomo, MD, Surgeon, Department of Orthopedic and Traumatology, Faculty of Medicine, Universitas Airlangga, Manyar Tirtosari Street IV/7, Surabaya 60118, East Java, Indonesia. dwikora-novembri-u@fk.unair.ac.id
Received: September 1, 2022
Peer-review started: September 1, 2022
First decision: December 19, 2022
Revised: December 22, 2022
Accepted: February 2, 2023
Article in press: February 2, 2023
Published online: February 18, 2023
Processing time: 169 Days and 11.4 Hours
Abstract
BACKGROUND

Globally, complete neurological recovery of spinal cord injury (SCI) is still less than 1%, and 90% experience permanent disability. The key issue is that a pharmacological neuroprotective-neuroregenerative agent and SCI regeneration mechanism have not been found. The secretomes of stem cell are an emerging neurotrophic agent, but the effect of human neural stem cells (HNSCs) secretome on SCI is still unclear.

AIM

To investigate the regeneration mechanism of SCI and neuroprotective-neuroregenerative effects of HNSCs-secretome on subacute SCI post-laminectomy in rats.

METHODS

An experimental study was conducted with 45 Rattus norvegicus, divided into 15 normal, 15 control (10 mL physiologic saline), and 15 treatment (30 μL HNSCs-secretome, intrathecal T10, three days post-traumatic). Locomotor function was evaluated weekly by blinded evaluators. Fifty-six days post-injury, specimens were collected, and spinal cord lesion, free radical oxidative stress (F2-Isoprostanes), nuclear factor-kappa B (NF-κB), matrix metallopeptidase 9 (MMP9), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), B cell lymphoma-2 (Bcl-2), nestin, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) were analyzed. The SCI regeneration mechanism was analyzed using partial least squares structural equation modeling (PLS SEM).

RESULTS

HNSCs-secretome significantly improved locomotor recovery according to Basso, Beattie, Bresnahan (BBB) scores and increased neurogenesis (nestin, BDNF, and GDNF), neuroangiogenesis (VEGF), anti-apoptotic (Bcl-2), anti-inflammatory (IL-10 and TGF-β), but decreased pro-inflammatory (NF-κB, MMP9, TNF-α), F2-Isoprostanes, and spinal cord lesion size. The SCI regeneration mechanism is valid by analyzed outer model, inner model, and hypothesis testing in PLS SEM, started with pro-inflammation followed by anti-inflammation, anti-apoptotic, neuroangiogenesis, neurogenesis, and locomotor function.

CONCLUSION

HNSCs-secretome as a potential neuroprotective-neuroregenerative agent for the treatment of SCI and uncover the SCI regeneration mechanism.

Keywords: Secretome; Regeneration mechanism; Spinal cord injury; Locomotor; Biomarkers

Core Tip: The human neural stem cell secretomes is effective in spinal cord injury (SCI) treatment, based on locomotor function improvement, decreased size of spinal cord lesions, and biomarkers expression. Based on partial least squares structural equation modeling analysis, the regeneration mechanism of SCI started with pro-inflammation, anti-inflammation, anti-apoptotic, neuroangiogenesis, neurogenesis, finally, locomotor improvement.