Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. May 26, 2024; 16(5): 575-590
Published online May 26, 2024. doi: 10.4252/wjsc.v16.i5.575
Hepatocyte growth factor enhances the ability of dental pulp stem cells to ameliorate atherosclerosis in apolipoprotein E-knockout mice
Han Duan, Ning Tao, Lin Lv, Kai-Xin Yan, Yong-Gang You, Zhuang Mao, Chang-Yao Wang, Xue Li, Jia-Yan Jin, Chu-Tse Wu, Hua Wang
Han Duan, Chang-Yao Wang, Hua Wang, School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China
Ning Tao, Lin Lv, Zhuang Mao, Xue Li, Chu-Tse Wu, Hua Wang, Beijing Institute of Radiation Medicine, Beijing 100850, China
Kai-Xin Yan, Department of Cardiology, The Sixth Medical Centre, Chinese People’s Liberation Army General Hospital, Beijing 100037, China
Yong-Gang You, Department of Orthopaedics, The Fourth Medical Centre, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
Jia-Yan Jin, Third Cadet Regiment, School of Basic Medical Science, Air Force Medical University, Xi’an 710032, Shaanxi Province, China
Co-first authors: Han Duan and Ning Tao.
Author contributions: Duan H and Tao N contributed equally to this study. These contributions include study design, acquisition and analysis of experimental data, and writing the actual manuscript. Wang H contributed to the conceptualization and writing - review & editing; Duan H, Tao N, and Lv L were involved in the data curation; Duan H, Tao N, Lv L, Yan KX, You YG, Mao Z, Wang CY, Li X, and Jin JY participated in the formal analysis; Duan H and Tao N contributed to the methodology of this manuscript; Wu CT was major in the supervision of this article; Duan H wrote original draft.
Institutional animal care and use committee statement: All procedures that involved animals were approved by the Institutional Animal Care and Use Committee of Beijing Institute of Radiation Medicine (IACUC-DWZX-2021-714).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
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: Hua Wang, PhD, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing 100850, China. 18511712135@163.com
Received: January 18, 2024
Revised: March 18, 2024
Accepted: April 9, 2024
Published online: May 26, 2024
Processing time: 127 Days and 7.6 Hours
Abstract
BACKGROUND

Atherosclerosis (AS), a chronic inflammatory disease of blood vessels, is a major contributor to cardiovascular disease. Dental pulp stem cells (DPSCs) are capable of exerting immunomodulatory and anti-inflammatory effects by secreting cytokines and exosomes and are widely used to treat autoimmune and inflammation-related diseases. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that plays a key role in many inflammatory and autoimmune diseases.

AIM

To modify DPSCs with HGF (DPSC-HGF) and evaluate the therapeutic effect of DPSC-HGF on AS using an apolipoprotein E-knockout (ApoE-/-) mouse model and an in vitro cellular model.

METHODS

ApoE-/- mice were fed with a high-fat diet (HFD) for 12 wk and injected with DPSC-HGF or Ad-Null modified DPSCs (DPSC-Null) through tail vein at weeks 4, 7, and 11, respectively, and the therapeutic efficacy and mechanisms were analyzed by histopathology, flow cytometry, lipid and glucose measurements, real-time reverse transcription polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay at the different time points of the experiment. An in vitro inflammatory cell model was established by using RAW264.7 cells and human aortic endothelial cells (HAOECs), and indirect co-cultured with supernatant of DPSC-Null (DPSC-Null-CM) or DPSC-HGF-CM, and the effect and mechanisms were analyzed by flow cytometry, RT-PCR and western blot. Nuclear factor-κB (NF-κB) activators and inhibitors were also used to validate the related signaling pathways.

RESULTS

DPSC-Null and DPSC-HGF treatments decreased the area of atherosclerotic plaques and reduced the expression of inflammatory factors, and the percentage of macrophages in the aorta, and DPSC-HGF treatment had more pronounced effects. DPSCs treatment had no effect on serum lipoprotein levels. The FACS results showed that DPSCs treatment reduced the percentages of monocytes, neutrophils, and M1 macrophages in the peripheral blood and spleen. DPSC-Null-CM and DPSC-HGF-CM reduced adhesion molecule expression in tumor necrosis factor-α stimulated HAOECs and regulated M1 polarization and inflammatory factor expression in lipopolysaccharide-induced RAW264.7 cells by inhibiting the NF-κB signaling pathway.

CONCLUSION

This study suggested that DPSC-HGF could more effectively ameliorate AS in ApoE-/- mice on a HFD, and could be of greater value in stem cell-based treatments for AS.

Keywords: Atherosclerosis; Apolipoprotein E-knockout mice; Cell therapy; Dental pulp stem cells; Hepatocyte growth factor

Core Tip: In this study, we found that dental pulp stem cells (DPSCs) treatment reduced atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE-/-) mice fed a high-fat diet and that Ad-hepatocyte growth factor (HGF) modified DPSCs (DPSC-HGF) treatment was more effective than Ad-Null modified DPSCs (DPSC-Null) treatment, which depended on the reduced expression of aortic endothelial cell adhesion molecule and inflammatory macrophages. In addition, DPSC-HGF had a greater inhibitory effect on the nuclear factor-κB signaling pathway in RAW264.7 cells and HAOECs cells under inflammatory stimulation than DPSC-Null. Taken together, these data suggest for the first time that DPSCs treatment can ameliorate AS in ApoE-/- mice and that DPSC-HGF has more impressive therapeutic potential than DPSC-Null and might be a new therapy for AS patients in the future.