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
ARTICLE HIGHLIGHTS
Research 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.

Research motivation

HNSCs-secretome is expected to be the basis for use in SCI cases in the primary research stage, translational research, and neurological research for the benefit of managing SCI disease problems.

Research objectives

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

Research 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). The strategies to increase the HNSCs-secretome production capacity include hypoxic preconditioning, tissue engineering, and growth medium composition. Locomotor function was evaluated weekly by blinded evaluators. Fifty-six days post-injury, specimens were collected, immunohistochemical-enzyme-linked immunosorbent assay assessment, and hematoxylin-eosin staining. We analyzed 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), and spinal cord lesion. The regeneration mechanism of SCI was analyzed using partial least squares structural equation modeling (PLS SEM).

Research results

The regeneration mechanism of SCI 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. HNSCs-secretome significantly improved locomotor recovery, reduced spinal cord lesion size, 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.

Research conclusions

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

Research perspectives

Future research investigating the chronic phase of SCI models may provide further evidence regarding the mechanism of SCI regeneration given HNSCs-secretome injection.